PT2256106E - 3,4-disubstituted 1h-pyrazole compounds and their use as cyclin dependent kinases (cdk) and glycogen synthase kinase-3 (gsk-3) modulators - Google Patents

Abstract

The invention provides compounds of the formula (0) or salts or tautomers or N-oxides or solvates thereof for use in the prophylaxis or treatment of disease states and conditions such as cancers mediated by cyclin-dependent kinase and glycogen synthase kinase-3. In formula (0): X is a group R1-A-NR4-or a 5-or 6-membered carbocyclic or heterocyclic ring; A is a bond, SO2, C=O, NRg(C=O) or O(C=O) wherein Rg is hydrogen or C1-4 hydrocarbyl optionally substituted by hydroxy or C1-4 alkoxy; Y is a bond or an alkylene chain of 1, 2 or 3 carbon atoms in length; R1 is hydrogen; a carbocyclic or heterocyclic group having from 3 to 12 ring members; or a C1-8 hydrocarbyl group optionally substituted by one or more substituents selected from halogen (e.g. fluorine), hydroxy, C1-4 hydrocarbyloxy, amino, mono- or di-C1-4 hydrocarbylamino, and carbocyclic or heterocyclic groups having from 3 to 12 ring members, and wherein 1 or 2 of the carbon atoms of the hydrocarbyl group may optionally be replaced by an atom or group selected from O, S, NH, SO, SO2; R2 is hydrogen; halogen; C1-4 alkoxy (e.g. methoxy); or a C1-4 hydrocarbyl group optionally substituted by halogen (e.g. fluorine), hydroxyl or C1-4 alkoxy (e.g. methoxy); R3 is selected from hydrogen and carbocyclic and heterocyclic groups having from 3 to 12 ring members; and R4 is hydrogen or a C1-4 hydrocarbyl group optionally substituted by halogen (e.g. fluorine), hydroxyl or C1-4 alkoxy (e.g. methoxy).

Description

3,4-DISSUBSTITUED 1H-PYRAZOLE COMPOUNDS AND ITS USE AS CYCLINE (CDK) AND GLYCOGENIC KINETICS MODIFIERS SYNTHASE-KINASE-3 (GSK-3)

This invention relates to pyrazole compounds which inhibit or modulate the activity of cyclin-dependent (CDK) and glycogen synthase-kinase-3 (GSK-3) kinases, the use of the compounds in the treatment or prophylaxis of conditions or pathological conditions mediated by cyclin and glycogen synthase kinase-3 dependent kinases, and to novel compounds having cyclin-dependent kinase or kinase-modifying activity or glycogen synthase kinase-3. Also provided are pharmaceutical compositions containing the compounds and novel chemical intermediates.

Background of the Invention

Protein kinases constitute a large family of structurally related enzymes that are responsible for controlling a wide variety of signal transduction processes within the cell (Hardie, G. and Hanks, S. (1995) The Protein Kinase Facts Book I and II, Academic Press, San Diego, CA). The kinases can be classified into families based on the substrates that they phosphorylate (e.g., protein tyrosine, protein-serine / threonine, lipids, etc.). Sequence motifs corresponding generally to each of these kinase families have been identified (eg, Hanks, SK, Hunter, T., FASEB J., 9: 576-596 (1995); Knighton, et al., Science, 253: , Et al., Cell, 70: 419-429 (1992), Kunz et al., Cell, 73: 585-596 (1993), Garcia-Bustos, et al., EMBO J., 13: 2352-2361 (1994)).

Protein kinases can be characterized by their regulatory mechanisms. These mechanisms include, for example, autophosphorylation, transphosphorylation by other kinases, protein-protein interactions, protein-lipid interactions and protein-polynucleotide interactions. A particular protein kinase can be regulated by more than one mechanism.

The kinases regulate many different cellular processes including, but not limited to, proliferation, differentiation, apoptosis, mobility, transcription, translation and other signaling processes by the addition of phosphate groups to target proteins. These phosphorylation events act as molecular switches that can modulate or regulate the biological function of the target protein. Phosphorylation of target proteins occurs in response to a variety of extracellular signals (hormones, neurotransmitters, growth and differentiation factors, etc.), cell cycle events, environmental or nutritional stresses, etc. The appropriate protein kinase acts in the signaling pathways to activate or inactivate (directly or indirectly), for example, a metabolic enzyme, regulatory protein, receptor, cytoskeletal protein, ion channel or pump, or transcription factor. Uncontrolled signaling due to poor control of protein phosphorylation has been implicated in a number of diseases, including, for example, inflammation, cancer, allergy / asthma, diseases and conditions of the immune system, diseases and conditions of the central nervous system, and angiogenesis. The process of dividing the eukaryotic cells can be broadly divided into a series of sequential phases designated Gl, S, G2 and M. It has been shown that the correct progression through the various phases of the cell cycle depends critically on the spatial regulation and temporal domain of a family of proteins known as cyclin-dependent kinases (CDK) and a varied set of their cognate partners of the protein termed cyclins. CDKs are cdc2 homologous serine-threonine kinase proteins (also known as CDK1) which are capable of using ATP as a substrate in the phosphorylation of various polypeptides in a context dependent sequence. Cyclins are a family of proteins characterized by a region of homology, containing approximately 100 amino acids, referred to as " cyclin box " which is used in the binding, and which defines selectivity for specific CDK partner proteins. Modulation of expression levels, degradation rates and activation levels of various CDKs and cyclins throughout the cell cycle leads to the cyclic formation of a series of CDK / cyclin complexes in which CDKs are enzymatically active. The formation of these complexes controls the passage through discrete cell cycle control points and thereby allows the cell division process to proceed. Failure to meet the prerequisite biochemical criteria at a given cell cycle control point, i. and. the failure to form a required CDK / cyclin complex can lead to cell cycle arrest and / or cellular apoptosis. Aberrant cell proliferation, as manifested in cancer, can often be attributed to loss of correct cell cycle control. Accordingly, inhibition of the enzymatic activity of CDK provides a means by which cells in abnormal division may have their division arrested and / or killed. The variety of CDKs, and CDK complexes, and their critical roles in cell cycle mediation provide a broad spectrum of potential therapeutic targets selected based on a defined biochemical rationale. The progression from G1 phase to S phase of the cell cycle is mainly regulated by CDK2, CDK3, CDK4 and CDK6 through association with members of D-type and E-cyclins. D-type cyclins appear to be determinant to allow passage beyond restriction site Gl, while the CDK2 / cyclin E complex is key to the transition from the G1 phase to the S. It is believed that the subsequent progression through the S phase and the G2 entry requires the CDK2 / cyclin A complex. Mitosis, and the transition from the G2 phase to the triggering M, are regulated by CDK1 complexes and the cyclins type A and B.

During Gl phase the Retinoblastoma protein (Rb) and related cavity proteins such as pl30 are substrates for the CDK (2,4,4 & 6) / cyclin complexes. Progression through Gl is in part facilitated by hyperphosphorylation and, thus, by inactivation, of Rb and p30 by the CDK (4/6) / cyclin-D complexes. Hyperphosphorylation of Rb and p30 causes the release of transcription factors, such as E2F, and thereby the expression of genes required for progression through Gl and for entry into the S phase, such as the gene for cyclin E. Expression of cyclin E facilitates the formation of the CDK2 / cyclin E complex, which increases or maintains E2F levels through the additional phosphorylation of Rb. The CDK2 / cyclin E complex also phosphorylates other proteins required for DNA replication, such as NPAT that has been implicated in histone biosynthesis. The progression of Gl and the Gl / S transition are also regulated via the mitogen-stimulated Myc pathway, which enters the CDK2 / cyclin E pathway. CDK2 is also related to the p53-mediated DNA damage response pathway through of the regulation of p21 levels by p53. P21 is a CDK2 / cyclin E protein inhibitor and is thus capable of blocking or retarding the Gl / S transition. The CDK2 / cyclin E complex may thus represent a point at which the biochemical stimuli of the Rb, Myc and p53 pathways are to some extent integrated. Therefore, CDK2 and / or CDK2 / cyclin E complex represent good targets for therapies designed to stop or regain control of the cell cycle in aberrant cell division. The exact role of CDK3 in the cell cycle is not clear. To date, no cognate cyclin partner has been identified, but a dominant negative form of CDK3 delays the cells in Gl, thereby suggesting that CDK3 plays a role in regulating the Gl / S transition.

Although most CDKs have been implicated in cell cycle regulation, there is evidence that certain members of the CDK family are involved in other biochemical processes. This is exemplified by CDK5 which is required for correct neuronal development and which has also been implicated in the phosphorylation of various neuronal proteins, such as Tau, NUDE-1, synapsinal, DARPP32 and the Muncl8 / SyntaxinalA complex. Neuronal CDK5 is conventionally activated by binding to p35 / p39 proteins. However, CDK5 activity can be deregulated by the binding of p25, a truncated version of p35. Conversion of p35 into p25, and subsequent dysregulation of CDK5 activity, can be induced by ischemia, excitotoxicity and β-amyloid peptide. Accordingly, p25 has been implicated in the pathogenesis of neurodegenerative diseases, such as Alzheimer's and is therefore of interest as a target for therapeutics directed against these diseases. CDK7 is a nuclear protein having cdc2 CAK activity and binding to cyclin H. CDK7 has been identified as a component of the TFIIH transcription complex, which has the C-terminal domain (CTD) activity of RNA polymerase II . This was associated with the regulation of HIV-1 transcription via a Tat-mediated biochemical pathway. CDK8 binds cyclin C and was implicated in CTD phosphorylation of RNA polymerase II. Similarly, the CDK9 / cyclin-T1 complex (P-TEFb complex) was involved in the control of RNA polymerase II elongation. PTEF-b is also required for the activation of HIV-1 genome transcription by Tat transactivator Tat through its interaction with cyclin T1. CDK7, CDK8, CDK9 and the P-TEFb complex are therefore potential targets for antiviral therapies. At a molecular level, mediation of the CDK / cyclin complex activity requires a series of phosphorylation or dephosphorylation events, stimulators and inhibitors. CDK phosphorylation is performed by a group of CDK activating kinases (CAKs) and / or kinases, such as weel, Mytl and Mikl. Dephosphorylation is performed by phosphatases, such as cdc25 (a & c), pp2a or KAP.

The CDK / cyclin complex activity can further be regulated by two families of endogenous cellular protein inhibitors: the Kip / Cip family or the INK family. INK proteins specifically bind CDK4 and CDK6. Pl6ink4 (also known as MTS 1) is a potential tumor suppressor gene that is mutated, or deleted, in a large number of primary cancers. The Kip / Cip family contains proteins, such as p21ciP1'Wafl, ρ27κ1Ρτ and p57KiP2. As discussed previously, p21 is induced by p53 and is capable of inactivating the CDK2 / cyclin (E / A) and CDK4 / cyclin complexes (D1 / D2 / D3). Atypically low levels of p27 expression were observed in breast, colon and prostate cancers. In contrast, overexpression of cyclin E in solid tumors has been shown to correlate with a poor prognosis for the patient. Cyclin D1 overexpression was associated with esophageal, breast, squamous and non-small cell lung carcinomas.

The essential roles of CDK and its associated proteins in the coordination and conduction of the cell cycle in proliferating cells have been outlined above. Some of the biochemical pathways in which CDKs play a key role have also been described. The development of monotherapies for the treatment of proliferative disorders, such as cancers, using generically targeted therapies for CDK, or for specific CDKs is therefore potentially very desirable. Possibly, CDK inhibitors could also be used to treat other conditions, such as viral infections, autoimmune diseases and neurodegenerative diseases, among others. Targeted therapies for CDK may also provide clinical advantages in treating the previously described diseases when used in combination therapy with existing or novel therapeutic agents. Potentially, anticancer therapies directed to CDK could have advantages over many standard antitumor agents since they would not interact directly with DNA and would therefore reduce the risk of secondary tumor development. Glycogen synthase-kinase-3 (GSK3) is a serine-threonine kinase that occurs as two ubiquitously expressed isoforms in humans (GSK3a & beta GSK3p). GSK3 has been implicated as having roles in embryonic development, protein synthesis, cell proliferation, cell differentiation, microtubule dynamics, cell motility and cellular apoptosis. As such, GSK3 has been implicated in the progression of disease states, such as diabetes, cancer, Alzheimer's disease, stroke, epilepsy, motor neuron disease and / or head trauma. Phylogenetically, GSK3 is very closely related to cyclin-dependent kinases (CDK). The consensus sequence of the peptide substrate recognized for GSK3 is (Ser / Thr) -XXX- (pSer / pThr), where X is any amino acid (at positions n + 1, n + 2, n + 3 )) and pSer and pThr are phosphoserine and phosphotreonine, respectively (n + 4). The GSK3

phosphorylates the first serine, or threonine, in position (n). The phosphoserine, or phosphotreonine, at the (n + 4) position appears to be necessary to prepare the GSK3 to give maximum cyclization of the substrate. Phosphorylation of GSK3a on Ser21, or GSK3p on Ser9, leads to inhibition of GSK3. Mutagenesis and competition studies of peptides have led to the model that the phosphorylated N-terminal end of GSK3 is able to compete with the phosphopeptide substrate (S / TXXXpS / pT) through an auto-inhibiting mechanism. There is also evidence suggesting that GSK3a and

GSK3β may be subtly regulated by phosphorylation of tyrosines 279 and 216, respectively. Mutation of these residues in a Phe resulted in a reduction of the kinase activity in vivo. The X-ray crystallographic structure of GSK33 has helped shed light on all aspects of GSK3 activation and regulation. GSK3 is part of the mammalian insulin response pathway and is capable of phosphorylating and thereby inactivating glycogen synthase. Positive regulation of glycogen synthase activity and hence glycogen synthesis through inhibition of GSK3 has thus been considered as a potential means to combat type II or non-insulin dependent diabetes mellitus (NIDDM): a condition in which body tissues become resistant to stimulation by insulin. The cellular response to insulin in the hepatic, adipose or muscular tissues is triggered by the binding of insulin to an extracellular insulin receptor. This leads to phosphorylation, and subsequent recruitment to the plasma membrane, of the insulin receptor substrate (IRS) proteins. Further phosphorylation of IRS proteins initiates the recruitment of phosphoinositide-3-kinase (PI3K) to the plasma membrane where it is able to release the secondary messenger phosphatidylinositol 3,4,5-trisphosphate (PIP3). This facilitates the co-localization of 3-phosphoinositide (PDK1) -dependent protein kinase 1 and protein kinase B (PKB or Akt) to the membrane, where PDK1 activates PKB. PKB is capable of phosphorylating and thereby inhibiting GSK3a and / or GSKp by phosphorylation of Ser9, or ser21, respectively. Inhibition of GSK3 then triggers the positive regulation of glycogen synthase activity. Therapeutic agents capable of inhibiting GSK3 may thus be capable of inducing cellular responses analogous to that observed in insulin stimulation. Another in vivo substrate of GSK3 is the eukaryotic initiator of protein synthesis 2B (eIF2B). The eIF2B is inactivated by phosphorylation and is thus capable of suppressing protein biosynthesis. Inhibition of GSK3, e.g. by inactivation of the " target protein " of rapamycin in mammals " (mTOR), can thus positively regulate protein biosynthesis. Finally, there is some evidence for the regulation of GSK3 activity by the mitogen-activated protein kinase (MAPK) pathway through the phosphorylation of GSK3 by kinases such as mitogen-activated protein kinase-activated protein kinase 1 (MAPKAP-K1 or RSK ). These data suggest that GSK3 activity can be modulated by mitogen, insulin and / or amino acid stimuli.

It has also been shown that ΰ3Κ3β is a key component in the Wnt signaling pathway of vertebrates. It has been shown that this biochemical pathway is critical for normal embryonic development and regulates cell proliferation in normal tissues. GSK3 is inhibited in response to Wnt stimuli. This may lead to dephosphorylation of GSK3 substrates, such as Axin, the genetic product of adenomatous coli polyposis (APC) and β-catenin. Aberrant regulation of the Wnt pathway has been associated with many cancers. Mutations in APC and / or β-catenin are common in colorectal cancer and other tumors. Β-catenin has also been shown to be important in cell adhesion. Thus, GSK3 can also modulate cell adhesion processes to some extent. In addition to the biochemical pathways already described, there are also data implicating GSK3 in the regulation of cell division through cyclin-D1 phosphorylation, in the phosphorylation of transcription factors such as c-Jun, CCAAT binding protein / enhancer (C / ), c-Myc and / or other substrates, such as Activated T-Cell Nuclear Factor (NFATc), Thermal Shock Factor-1 (HSF-1) and c-AMP response element binding protein (CREB ). GSK3 also appears to play a role, though tissue-specific, in the regulation of cellular apoptosis. The role of GSK3 in the modulation of cellular apoptosis through a pro-apoptotic mechanism may be particularly relevant for clinical conditions in which neuronal apoptosis may occur. Examples are cranial trauma, stroke, epilepsy, Alzheimer's and motor neuron diseases, progressive supranuclear palsy, corticobasal degeneration, and Pick's disease. In vitro it has been shown that GSK3 is capable of hyperphosphorylating the Tau protein associated with the microtubule. Tau hyperphosphorylation disrupts its normal binding to microtubules and can also lead to the formation of intracellular Tau filaments. It is thought that the progressive accumulation of these filaments leads to eventual dysfunction and neuronal degeneration. Inhibition of Tau phosphorylation, through inhibition of GSK3, can thus provide a means to limit and / or prevent neurodegenerative effects. Prior Art WO 02/34721 to Du Pont discloses a class of indeno [1,2-c] pyrazol-4-ones as inhibitors of cyclin-dependent kinases. WO 01/81348 to Bristol Myers Squibb discloses the use of 5-thio, sulfinyl- and sulfonylpyrazolo [3,4-b] -pyridines as inhibitors of cyclin-dependent kinase. WO 00/62778 also from Bristol Myers Squibb discloses a class of protein tyrosine kinase inhibitors. W002 / 068406 to Amgen Inc. describes pyrazole compounds that inhibit protein kinases, such as CDK-2 and CDK-5. WO 01 / 72745A1 to Cyclacel discloses 4-substituted 4-heteroaryl-pyrimidines and their preparation, pharmaceutical compositions containing them and their use as inhibitors of cyclin-dependent (CDK) kinases and, accordingly, their use in treatment of proliferative disorders such as cancer, leukemia, psoriasis, and the like. Agouron WO 99/21845 discloses 4-aminothiazole derivatives to inhibit cyclin-dependent (CDK) kinases, such as CDK1, CDK2, CDK4 and CDK6. The invention is also directed to the therapeutic or prophylactic use of pharmaceutical compositions containing such compounds and methods of treating malignancies and other disorders by administering effective amounts of such compounds. Agouron WO 01/53274 discloses as inhibitors of CDK kinase a class of compounds which may comprise an amide-substituted benzene ring attached to an N-containing heterocyclic group. WO 01/98290 (Pharmacia & Upjohn) discloses a class of 3-aminocarbonyl-2-carboxamido thiophene derivatives as protein kinase inhibitors.

Agouron WO 01/53268 and WO 01/02369 disclose compounds that mediate or inhibit cell proliferation through inhibition of protein kinases, such as cyclin-dependent kinase or tyrosine kinase. The Agouron compounds have an aryl or heteroaryl ring attached directly, or through a CH = CH or CH = N group, to the 3-position of an indazole ring.

WO 00/39108 and WO 02/00651 (both from Du Pont Pharmaceuticals) disclose heterocyclic compounds which are inhibitors of trypsin-like serine protease enzymes, especially factor Xa and thrombin. The compounds are specified as being useful as anticoagulants or for the prevention of thromboembolic disorders.

US 2002/0091116 (Zhu et al.), WO 01/19798 and WO 01/64642 each disclose various groups of heterocyclic compounds as inhibitors of Factor Xa. A number of substituted 1-substituted pyrazolecarboxamides are disclosed and exemplified.

US 6,127,882, WO 01/70668, WO 00/68191, WO 97/48672, WO 97/19052 and WO 97/19062 (all of Allergan) each disclose compounds having retinoid-like activity for use in the treatment of hyperproliferative diseases including cancers. WO 02/070510 (Bayer) discloses a class of amino dicarboxylic acid compounds for use in the treatment of cardiovascular diseases. Although pyrazoles are generically mentioned herein, there are no specific examples of pyrazoles. WO 97/03071 (Knoll AG) discloses a class of heterocyclyl-carboxamide derivatives for use in the treatment of disorders of the central nervous system. Pyrazoles are generally mentioned as examples of heterocyclic groups, but no specific pyrazole compounds are disclosed or exemplified. WO 97/40017 (Novo Nordisk) discloses compounds which are protein tyrosine phosphatase modulators. WO 03/020217 (Univ. Connecticut) discloses a class of pyrazole-3-carboxamides as modulators of the cannabinoid receptor for the treatment of neurological conditions. It is specified (page 15) that the compounds may be used in cancer chemotherapy but it is unclear whether the compounds are active as anticancer agents or whether they are administered for other purposes. WO 01/58869 (Bristol Myers Squibb) discloses cannabinoid receptor modulators which may be used inter alia to treat a variety of diseases. The primary use considered is the treatment of respiratory diseases, although reference is made to the treatment of cancer. WO 01/02385 (Aventis Crop Science) discloses 1- (quinolin-4-yl) -1H-pyrazole derivatives as fungicides. Unsubstituted pyrazoles at the 1-position are disclosed as synthetic intermediates. WO 2004/039795 (Fujisawa) discloses amides containing a pyrazole group substituted at the 1-position as inhibitors of apolipoprotein B secretion. The compounds are specified as being useful in the treatment of conditions, such as hyperlipidemia. WO 2004/000318 (Cellular Genomics) discloses various amino substituted monocycles as kinase modulators. None of the exemplified compounds are pyrazoles.

Summary of the Invention

Compounds of formula (II) having cyclin-dependent kinase inhibitory or modulating activity, and which are believed to be useful in preventing or treating pathological conditions or conditions mediated by kinases.

Thus, for example, it is contemplated that the compounds of formula (II) will be useful in alleviating or reducing the incidence of cancer.

Accordingly, in a first aspect, the invention provides a combination comprising: (i) A compound of formula (II):

or salts or tautomers or N-oxides or solvates thereof; wherein Y is a bond or an alkylene chain of 1, 2 or 3 carbon atoms in length; R1 is a carbocyclic or heterocyclic group having from 3 to 12 ring members, wherein the carbocyclic or heterocyclic groups are unsubstituted or substituted with one or more substituent groups R10; R2 is hydrogen or methyl; R 3 is selected from non-aromatic carbocyclic and heterocyclic groups having from 3 to 12 ring members, wherein the carbocyclic or heterocyclic groups are unsubstituted or substituted with one or more substituent groups R 10; and R 10 is selected from halogen, hydroxy, trifluoromethyl, cyano, nitro, carboxyl, amino, mono- or dihydrocarbylamino

C 1-4 carbocyclic and heterocyclic groups having from 3 to 12 ring members; a group Ra-Rb wherein Ra is a bond, O, CO, X1C (X2), C (X2) X2, X1C (X2) X1, S, SO, SO2, NRC, SO2NRc or NRcS02; and Rb is selected from hydrogen, carbocyclic and heterocyclic groups having from 3 to 12 ring members and a C1-8 alkyl group optionally substituted with one or more substituents selected from hydroxy, oxo, halogen, cyano, nitro, carboxyl, amino, mono - or di-C 1-4 hydrocarbylamino, carbocyclic and heterocyclic groups having from 3 to 12 ring members,

Rc is selected from hydrogen and C1-4 hydrocarbyl; and X 1 is O, S or NRC and X 2 is = O, = S or = NRC; and provided that when the substituent group R 10 comprises or includes a carbocyclic or heterocyclic group, said carbocyclic or heterocyclic group may be unsubstituted or may itself be substituted with one or more substituent groups R 10 and additionally wherein (a) these other substituent groups R 10 include carbocyclic or heterocyclic groups, which are not themselves yet substituted; or (b) said other substituents do not include carbocyclic or heterocyclic groups, but are otherwise selected from the groups listed above in the definition of R 10; and (ii) one or more other therapeutic agents.

In a second aspect, the invention provides the compound of formula (II) as defined above for use in the treatment of a disease which is:

Viral infections, for example herpes viruses, smallpox virus, Epstein-Barr virus, Sindbis virus, adenovirus, HIV, HPV, HCV and HCMV; prevention of AIDS development in HIV-infected individuals; or - Type II or non-insulin-dependent diabetes mellitus; or - autoimmune diseases; or - Cranial trauma; or - stroke; or - Epilepsy; or - Neurodegenerative diseases, Alzheimer's disease, AIDS-related dementia, Parkinson's disease, amyotrophic lateral sclerosis, retinitis pigmentosa, spinal muscular atropy and cerebellar degeneration or, such as, motor neuron Alzheimer's disease, progressive supranuclear palsy , cortico-basal degeneration and Pick's disease; or - chronic inflammatory diseases, for example, systemic lupus erythematosus, autoimmune mediated glomerulonephritis, rheumatoid arthritis, psoriasis, inflammatory bowel disease, and autoimmune diabetes mellitus; or - cardiovascular diseases, for example, cardiac hypertrophy, restenosis, and atherosclerosis, or such as arrhythmia; or - Glomerulonephritis; or - Myelodysplastic syndrome; or

Ischemic injury associated with myocardial infarction, stroke and reperfusion injury; or - toxin-induced liver diseases of the liver; or - hematological diseases, eg chronic anemia and aplastic anemia; or

Degenerative diseases of the musculoskeletal system, eg, osteoporosis and arthritis, or - aspirin-sensitive rhinosinusitis; or - Cystic fibrosis; or - multiple sclerosis, or - renal diseases; or - Cancer pain; or - Cancer, in particular RB + sees tumors.

Any one or more of the following optional conditions, in any combination, may be applied to the compounds of formula (II) and its subgroups: (a-i) R1 is other than a purine nucleoside group containing unit. (a-ii) When Y-R 3 is cycloalkyl, then R 1 is other than a substituted or unsubstituted tetrahydronaphthalene, tetrahydroquinolinyl, tetrahydrochromanyl or tetrahydrothiochromanyl group. (a-iii) R 3 is other than a unit containing a 1,2,8,8a-tetrahydro-7-methyl-cyclopropa [c] pyrrolo [3,2, e] indole-4- (5H) - one. (a-iv) R 1 (CO) NH is other than 4- (tert-butyloxycarbonylamino) -3-methylimidazol-2-ylcarbonylamino. (b-i) R 3 is other than a bridging azabicyclo group. (b-ii) When R 1 or R 3 contains a moiety in which a heterocyclic ring having an S (= O) 2 ring member is fused to a carbocyclic ring, said carbocyclic ring is other than a substituted or unsubstituted benzene ring. Reference in the proviso (ai) to a purine nucleoside group, refers to substituted and unsubstituted purine groups having attached thereto a monosaccharide group (eg a pentose or hexose) or a derivative of a monosaccharide group, for example a deoxymonosaccharide group or a substituted monosaccharide group. The reference in the proviso (b-i) to a bridged azabicyclo group refers to bridged bicycloalkane ring systems in which one of the carbon atoms of bicycloalkane has been replaced with a nitrogen atom. In bridge ring systems, two rings share more than two atoms, see for example, Advanced Organic Chemistry, by Jerry March, 4th Edition, Wiley

Interscience, pages 131-133, 1992. The invention also provides the use of a compound of the formula (II) as defined herein for the manufacture of a medicament for the prophylaxis or treatment of a condition or pathological condition mediated by a cyclin-dependent kinase .

The conditions (a-i) to (a-iv) and (b-i) to (b-ii) in formula (II) above refer to the disclosures in the following prior art documents. (a-i) WO 03/014137 (a-ii) WO 97/48672, WO 97/19052 (a-iv) US 5,502,068 (b-i) WO 03/040147 (b-ii) WO 00/59902

Any one or more of the above optional conditions, (ai) to (a-iv) and (bi) to (b-ii) in any combination, may also apply to the compounds of formulas (IV), (IVa) ), (Vb), (Via) (VIb) and its subgroups as defined herein. The invention also provides: The use of the combination as defined herein for the manufacture of a medicament for the prophylaxis or treatment of a cyclin-dependent kinase-mediated condition or condition. Combination as defined herein for use in the prophylaxis or treatment of a condition or condition which is a proliferative disorder in which the proliferative disorder is a cancer. The invention also provides combinations of the invention for use in: A method of alleviating or reducing the incidence of a disease or condition comprising or resulting from abnormal cell growth in a mammal, which method comprises administering a combination as defined herein in an amount effective to inhibit abnormal cell growth. A method of alleviating or reducing the incidence of a cyclin or glycogen-dependent kinase-mediated condition or condition mediated by a cyclin-dependent kinase, which method comprises administering to a subject in need thereof a combination of subgroups as defined herein. A method for the prophylaxis or treatment of a cyclin-dependent kinase mediated condition or condition, which method comprises administering to a subject in need thereof a combination as defined herein. A method of treating a disease or condition comprising or resulting from abnormal cell growth in a mammal, which method comprises administering to the mammal a combination as defined herein in an amount effective to inhibit abnormal cell growth. A method of treating a disease or condition comprising or resulting from abnormal cell growth in a mammal, the method comprising administering to the mammal a combination as defined herein in an amount effective to inhibit a cyclin-dependent kinase (e.g., CDK2). A method of inhibiting a cyclin-dependent kinase which method comprises contacting the kinase with a kinase inhibitor combination as defined herein. A method of modulating a cellular process (e.g., Cell division) by inhibiting the activity of a cyclin dependent kinase using a combination and its subgroups as defined herein. A method for the treatment or prophylaxis of any of the conditions or conditions disclosed herein, which method comprises administering to a patient (e.g., a patient in need thereof) a combination (e.g., a therapeutically effective amount) as defined herein. A method of alleviating or reducing the incidence of a condition or condition disclosed herein, which method comprises administering to a patient (e.g., a patient in need thereof) a combination as defined herein. A method for the diagnosis and treatment of a cyclin-dependent kinase mediated condition or condition, which method comprises (II) screening a patient to determine whether a disease or condition of which the patient suffers or is likely to suffer is one would be susceptible to treatment with a combination having activity against cyclin-dependent kinases; and (ii) where it is indicated that the disease or condition from which the patient is thus susceptible, subsequently administer to the patient a combination as defined herein.

The compounds of the invention are also considered to be glycogen synthase kinase-3 (GSK3) inhibitors and therefore the invention also provides methods and uses of inhibition or modulation combinations as defined herein but wherein the kinase is glycogen synthase kinase -3.

In other aspects, the invention provides: A pharmaceutical composition comprising a combination as defined herein and a pharmaceutically acceptable carrier. • Combinations as defined herein for use in medicine. The use of a combination as defined herein for the manufacture of a medicament for the prophylaxis or treatment of any of the conditions or pathological conditions disclosed herein. The use of a combination as defined herein for the manufacture of a medicament for the treatment or prophylaxis of a condition or condition in a patient who has been screened and who has been determined to be suffering from or at risk of a disease or condition that would be susceptible to treatment with a compound having activity against cyclin-dependent kinase.

In each of the foregoing uses, methods and other aspects of the invention, as well as in any aspects and embodiments of the invention as set forth below, references to compounds of the formulas (II), (IV), (IVa), (Va), (Vb), (Via) or (VIb) and subgroups thereof as defined herein include in their scope the salts or solvates or tautomers or N-oxides of the compounds.

Preferences and General Settings

The following general preferences and definitions are applicable to each of the Y, R1 to R3 units, and to any sub-definition, subgroup or embodiment thereof, unless the context indicates otherwise.

In this specification, references to formula (II) include formulas (IV), (IVa), (Va), (Vb), (Way) or (VIb) and subgroups, examples or embodiments of formulas (IV), (IVa), (Va), (Vb), (Via) or (VIb), unless the context indicates otherwise.

Thus, for example, references to, inter alia, therapeutic uses, pharmaceutical formulations and processes for preparing compounds of formula (II) are also to be considered as referring to formulas (IV), (IVa) (IVb), (Vb), (Vb), (Vb), (Vb), (Vb), (Vb), (Vb), (Vb) or (VIb) and subgroups, examples or embodiments of the formulas (IV).

Similarly, where preferences, embodiments and examples are given for the compounds of the formula (II), they are also applicable to the formulas, (IV), (IVa), (Va), (Vb), (Way) or (VIb ) and subgroups, examples or embodiments of formulas (IV), (IVa), (Va), (Vb), (Way) or (VIb), unless the context otherwise requires.

References to " carbocyclic " and " heterocyclic " as used herein shall, unless the context otherwise indicates, include aromatic and non-aromatic ring systems. Thus, for example, the term " carbocyclic and heterocyclic groups " includes within its scope non-aromatic, unsaturated, partially saturated and fully saturated aromatic carbocyclic and heterocyclic ring systems. In general, such groups may be monocyclic or bicyclic and may contain, for example, 3 to 12 ring members, more generally 5 to 10 ring members. Examples of monocyclic groups are 3-, 4-, 5-, 6-, 7- and 8-membered endocyclic groups, more generally 3 to 7, and preferably 5 or 6 endocyclic members. Examples of bicyclic groups are those containing 8, 9, 10, 11 and 12 endocyclic members, and more generally 9 or 10 endocyclic members.

Carbocyclic or heterocyclic groups may be aryl or heteroaryl groups having from 5 to 12 ring members, more generally from 5 to 10 ring members. The term " aryl " as used herein refers to a carbocyclic group having aromatic character and the term " heteroaryl " is used herein to denote a heterocyclic group having aromatic character. The terms " aryl " and " heteroaryl " encompass polycyclic (e.g., bicyclic) ring systems wherein one or more rings are non-aromatic, with the proviso that at least one ring is aromatic. In such polycyclic systems, the group may be attached by the aromatic ring or a non-aromatic ring. The aryl or heteroaryl groups may be monocyclic or bicyclic groups and may be unsubstituted or substituted with one or more substituents, for example one or more R 10 groups as defined herein. The term " non-aromatic group " comprises non-aromatic unsaturated ring systems, partially saturated and fully saturated carbocyclic and heterocyclic ring systems. The terms " unsaturated " and " partially saturated " refer to rings in which the ring structure or structures contain atoms that share binding with more than one valence, i. the ring contains at least one multiple bond, e.g. a C = C, C = C or N = C bond. The term " fully saturated " refers to rings where there are no multiple bonds between endocyclic atoms. The saturated carbocyclic groups include cycloalkyl groups as defined below. Partially saturated carbocyclic groups include cycloalkenyl groups as defined below, for example, cyclopentenyl, cycloheptenyl and cyclooctenyl. Another example of a cycloalkenyl group is cyclohexenyl.

Examples of heteroaryl groups are monocyclic and bicyclic groups containing from five to twelve endocyclic members, and more generally from five to ten endocyclic members. The heteroaryl group may be, for example, a five-membered or six-membered monocyclic ring or a bicyclic structure formed from fused five- and six-membered rings or two fused six-membered rings or, by way of a further example, two cast five-membered rings. Each ring may contain up to about four heteroatoms typically selected from nitrogen, sulfur and oxygen. Typically the heteroaryl ring will contain up to 4 heteroatoms, more typically up to 3 heteroatoms, more generally up to 2, for example, a single heteroatom. In one embodiment, the heteroaryl ring contains at least one endocyclic nitrogen atom. The nitrogen atoms in the heteroaryl rings may be basic, as in the case of an imidazole or pyridine, or essentially non-basic as in the case of an indole or pyrrole nitrogen. In general, the number of basic nitrogen atoms present in the heteroaryl group, including any ring substituent amino groups, will be less than five.

Examples of five-membered heteroaryl groups include but are not limited to the pyrrole, furan, thiophene, imidazole, furazan, oxazole, oxadiazole, oxatriazole, isoxazole, thiazole, isothiazole, pyrazole, triazole and tetrazole groups.

Examples of six-membered heteroaryl groups include but are not limited to pyridine, pyrazine, pyridazine, pyrimidine and triazine.

A bicyclic heteroaryl group may be, for example, a group selected from: a) a benzene ring fused with a 5- or 6-membered ring containing 1, 2 or 3 ring heteroatoms; b) a pyridine ring fused to a 5- or 6-membered ring containing 1, 2 or 3 ring heteroatoms; c) a 5- or 6-membered fused pyrimidine ring containing 1 or 2 ring heteroatoms; d) a 5- or 6-membered fused pyrrole ring containing 1, 2 or 3 ring heteroatoms; e) a fused pyrazole ring with a 5- or 6-membered ring containing 1 or 2 ring heteroatoms; f) a 5- or 6-membered fused imidazole ring containing 1 or 2 ring heteroatoms; g) a 5- or 6-membered fused oxazole ring containing 1 or 2 ring heteroatoms; h) a fused isoxazole ring with a 5- or 6-membered ring containing 1 or 2 ring heteroatoms; i) a fused thiazole ring having a 5- or 6-membered ring containing 1 or 2 ring heteroatoms; j) a fused isothiazole ring having a 5- or 6-membered ring containing 1 or 2 ring heteroatoms; k) a thiophene ring fused with a 5- or 6-membered ring containing 1, 2 or 3 ring heteroatoms; l) a furan ring fused with a 5- or 6-membered ring containing 1, 2 or 3 ring heteroatoms; m) a fused oxazole ring with a 5- or 6-membered ring containing 1 or 2 ring heteroatoms; n) a fused isoxazole ring with a 5- or 6-membered ring containing 1 or 2 ring heteroatoms; o) a cyclohexyl ring fused with a 5- or 6-membered ring containing 1, 2 or 3 ring heteroatoms; and p) a 5- or 6-membered fused cyclopentyl ring containing 1, 2 or 3 ring heteroatoms.

Particular examples of bicyclic heteroaryl groups containing a five membered ring fused to another five membered ring include but are not limited to imidazotiazole (eg, imidazo [2,1-b] thiazole) and imidazoimidazole (eg, imidazo [1,2- a] imidazole).

Particular examples of bicyclic heteroaryl groups containing a six membered ring fused to a five membered ring include but are not limited to benzofuran, benzothiophene, benzoxazole, benzoxazole, isobenzoxazole, benzisoxazole, benzothiazole, benzisothiazole, isobenzofuran, indole, isoindole, indolizine (eg, [1,2,4] triazolo [1,5-a] pyrazolo [1,5-a] pyrimidine), indoline, isoindoline, pyrimidine), benzodioxole and pyrazolopyridine (eg, pyrazolo [1,5-a] pyridine).

Particular examples of bicyclic heteroaryl groups containing two fused six-membered rings include but are not limited to the quinoline, isoquinoline, chroman, thiochroman, chromio, isochromene, chromane, isochroman, benzodioxan, quinolizine, benzoxazine, benzodiazine, pyridopyridine, quinoxaline, quinazoline , cinnoline, phthalazine, naphthyridine and pteridine.

A subgroup of heteroaryl groups comprises pyridyl, pyrrolyl, furanyl, thienyl, imidazolyl, oxazolyl, oxadiazolyl, oxatriazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyrazolyl, pyrazinyl, pyrazinyl, pyrimidinyl, triazinyl, triazolyl, triazolyl, tetrazolyl, quinolinyl, isoquinolinyl, benzofuranyl, benzothiazolyl, benzothiazolyl, benzoxazolyl, benzothiazolyl, and benzisothiazole, isobenzofuranyl, indolyl, isoindolyl, indolizinyl, indolinyl, isoindolinyl, purinyl (eg, adenine, guanine), indazolyl, benzodioxolyl, chromenyl, isochromenyl, isochromanyl, benzodioxanyl, quinolizinyl , benzoxazinyl, benzodiazinyl, pyridopyridinyl, quinoxalinyl, quinazolinyl, cinnolinyl, phthalazinyl, naphthyridinyl and pteridinyl.

Examples of polycyclic aryl and heteroaryl groups containing an aromatic ring and a non-aromatic ring include the tetrahydronaphthalene, tetrahydroisoquinoline, tetrahydroquinoline, dihydrobenzothieno, dihydrobenzofuran, 2,3-dihydro-benzo [ 1,4] dioxine, benzo [1,3] dioxole, 4,5,6,7-tetrahydrobenzofuran, indoline and indane.

Examples of carbocyclic aryl groups include the phenyl, naphthyl, indenyl and tetrahydronaphthyl groups.

Examples of non-aromatic heterocyclic groups include unsubstituted or substituted heterocyclic groups (having one or more R 10 groups) having from 3 to 12 ring members, typically from 4 to 12 ring members and more generally from 5 to 10 ring members. Such groups may be, for example, monocyclic or bicyclic and typically have from 1 to 5 heteroatom ring members (more generally 1, 2, 3 or 4 heteroatom ring members) typically selected from nitrogen, oxygen and sulfur.

When sulfur is present, it may exist as -S-, -S (O) - or -S (O) 2-, when the nature of adjacent atoms and groups permits.

The heterocyclic groups may contain, for example, cyclic ether units (eg, as in tetrahydrofuran and dioxane), cyclic thioether units (eg as in tetrahydrothiophene and dithiane), cyclic amine units (eg, as in pyrrolidine), (eg as in butylrolactone), cyclic sulfonates (eg, as in sulfolane and sulfolene), cyclic sulfoxides, cyclic sulfonamides and their combinations (eg as in pyrrolidone), cyclic thioamides, , morpholine and thiomorpholine and their S-oxides and S, S-dioxides). Further examples of heterocyclic groups are those which contain a cyclic urea unit (e.g., as in imidazolidin-2-one).

In a subset of heterocyclic groups, heterocyclic groups contain cyclic ether units (eg, as in tetrahydrofuran and dioxane), cyclic thioether units (eg as in tetrahydrothiophene and dithiane), cyclic amine units (eg as in pyrrolidine) , cyclic sulfones (eg as in sulfolane and sulfolene), cyclic sulfoxides, cyclic sulfonamides and their combinations (eg, thiomorpholine).

Examples of non-aromatic monocyclic heterocyclic groups include the 5-, 6- and 7-membered monocyclic heterocyclic groups. Particular examples include morpholine, piperidine (eg, 1-piperidinyl, 2-piperidinyl, 3-piperidinyl and 4-piperidinyl), pyrrolidine (eg, 1-pyrrolidinyl, 2-pyrrolidinyl and 3-pyrrolidinyl), pyrrolidone, pyran or 4H-pyran), dihydrothiophene, dihydropyran, dihydrofuran, dihydrothiazole, tetrahydrofuran, tetrahydrothiophene, dioxane, tetrahydropyran (eg, 4-tetrahydropyranyl), imidazoline, imidazolidinone, oxazoline, thiazoline, 2-pyrazoline, pyrazolidine, piperazine and N-alkylpiperazines such as N-methylpiperazine. Other examples include thiomorpholine and its S-oxide and S, S-dioxide (particularly thiomorpholine). Still other examples include azetidine, piperidone, piperazone and N-alkylpiperidines, such as N-methylpiperidine.

A preferred subset of non-aromatic heterocyclic groups consists of saturated groups, such as azetidine, pyrrolidine, piperidine, morpholine, thiomorpholine, S, S-thiomorpholine dioxide, piperazine, N-alkylpiperazines and N-alkylpiperidines.

Another subset of non-aromatic heterocyclic groups consists of pyrrolidine, piperidine, morpholine, thiomorpholine, S, S-thiomorpholine dioxide, piperazine and N-alkylpiperazines such as N-methylpiperazine.

A particular subset of heterocyclic groups consists of pyrrolidine, piperidine, morpholine and N-alkylpiperazines (e.g., N-methylpiperazine) and, optionally, thiomorpholine.

Examples of non-aromatic carbocyclic groups include cycloalkane groups such as cyclohexyl and cyclopentyl, cycloalkenyl groups such as cyclopentenyl, cyclohexenyl, cycloheptenyl and cyclooctenyl, as well as cyclohexadienyl, cyclooctatetraene, tetrahydronaphthenyl and decalinyl .

Preferred non-aromatic carbocyclic groups are monocyclic rings and, most preferably, monocyclic saturated rings.

Typical examples are saturated three, four, five and six membered carbocyclic rings, e.g. the optionally substituted cyclopentyl and cyclohexyl rings.

A subset of non-aromatic carbocyclic groups include unsubstituted or substituted monocyclic groups (with one or more R 10 groups) and particularly saturated monocyclic groups, e.g. cycloalkyl groups. Examples of such cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl; more typically cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl, particularly cyclohexyl.

Other examples of non-aromatic cyclic groups include bridged ring systems, such as bicycloalkanes and azabicycloalkanes, although such bridging ring systems are generally less preferred. By " bridged ring systems " it is intended to refer to ring systems in which two rings share more than two atoms, see for example, Advanced Organic Chemistry, by Jerry March, 4th Edition, Wiley Interscience, pages 131-133, 1992. Examples of ring systems in bridge include bicyclo [2.2.1] heptane, aza-bicyclo [2.2.1] heptane, bicyclo [2.2.2] octane, aza-bicyclo [2.2.2] octane, bicyclo [3.2.1] octane and aza-bicyclo [ 3.2.1] octane. A particular example of a bridging ring system is the 1-aza-bicyclo [2.2.2] octan-3-yl group.

Where carbocyclic and heterocyclic groups are referred to herein, the carbocyclic or heterocyclic ring may, unless the context indicates otherwise, be unsubstituted or substituted with one or more substituent groups R10 selected from halogen, hydroxy, trifluoromethyl, cyano, nitro, carboxy, amino, C1-4 mono- or dihydrocarbylamino groups, carbocyclic and heterocyclic groups having from 3 to 12 ring members; a group Ra-Rb wherein Ra is a bond, O, CO, X1 X2), C (X2) X2, X1C (X2) X1, S, SO, SO2, NRC, SO2NRc or NRcS02; and Rb is selected from hydrogen, carbocyclic and heterocyclic groups having from 3 to 12 ring members, and a C1-8 hydrocarbyl group optionally substituted with one or more substituents selected from hydroxy, oxo, halogen, cyano, nitro, carboxyl, amino, mono - or C1-4 dihydrocarbylamino groups, carbocyclic and heterocyclic groups having from 3 to 12 ring members and wherein one or more carbon atoms of the C1-8 hydrocarbyl group may be optionally substituted with O, S, SO, SO2, NRC, X 2 C (X 2), C (X 2) X 2 or X 1 C (X 2) X 1;

Rc is selected from hydrogen and C1-4 hydrocarbyl; and X 1 is O, S or NRC and X 2 is = O, = S or = NRC.

When the substituent group R 10 comprises or includes a carbocyclic or heterocyclic group, said carbocyclic or heterocyclic group may be unsubstituted or may itself be substituted by one or more other substituent groups R 10. In a subgroup of compounds of formula (II), such other substituent groups R 10 may include carbocyclic or heterocyclic groups, which typically are not themselves further substituted. In another subgroup of compounds of formula (II), said other substituents do not include carbocyclic or heterocyclic groups but are otherwise selected from the groups listed above in the definition of R 10.

The substituents R 10 may be selected such that they contain not more than 20 non-hydrogen atoms, for example not more than 15 different hydrogen atoms, e.g. g is not more than 12, or 11, or 10, or 9, or 8, or 7, or 6, or 5 other than hydrogen.

When the carbocyclic and heterocyclic groups have a pair of substituents on adjacent ring atoms, the two substituents may be attached to form a cyclic group. Thus, two adjacent R 10 groups together with the carbon atoms or heteroatoms to which they are attached may form a 5-membered heteroaryl ring or a 5- or 6-membered non-aromatic carbocyclic or heterocyclic ring, wherein said heteroaryl and heterocyclic groups contain up to 3 heteroatom ring members selected from N, O and S. For example, a pair of adjacent substituents on adjacent carbon atoms of a ring may be attached through one or more heteroatoms and optionally substituted alkylene groups to form an oxa dioxa-, aza-, diaza- or oxa-aza-cycloalkyl.

Examples of such joined substituent groups include:

Examples of halogen substituents include fluoro, chloro, bromo and iodo. Fluorine and chlorine are particularly preferred.

In the definition of the above compounds of formula (II) and as used below, the term " hydrocarbyl " is a generic term encompassing aliphatic, alicyclic and aromatic groups having a fully carbon skeleton and consisting of carbon and hydrogen atoms, unless otherwise indicated.

In certain cases, as defined herein, one or more of the carbon atoms constituting the carbon skeleton may be substituted with a specified atom or group of atoms.

Examples of hydrocarbyl groups include the carbocyclic alkyl, cycloalkenyl, cycloalkenyl, carbocyclic aryl, alkenyl, alkynyl, cycloalkylalkyl, cycloalkenylalkyl, and aralkyl, aralkenyl and aralkynyl groups. Such groups may be unsubstituted or, where specified, substituted with one or more substituents as defined herein. The examples and preferences expressed below, apply to each of the hydrocarbyl-substituent groups or hydrocarbyl-containing substituent groups referred to in the various definitions of substituents for the compounds of formula (II) unless otherwise indicated in the context.

Preferred non-aromatic hydrocarbyl groups are saturated groups, such as alkyl and cycloalkyl groups.

Generally, by way of example, the hydrocarbyl groups may have up to eight carbon atoms, unless the context requires otherwise. In the subset of hydrocarbyl groups having 1 to 8 carbon atoms, particular examples are C 1-6 hydrocarbyl groups, such as C 1-4 hydrocarbyl groups (eg, C 1-3 hydrocarbyl groups or C 1-2 hydrocarbyl groups), the any particular value or combination of values selected from C 1, C 2, C 3, C 4, C 5, C 6, C 7 and Os hydrocarbyl groups. The term " alkyl " encompasses straight chain and branched chain alkyl groups. Examples of alkyl groups include methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, 2-pentyl, 3-pentyl, 2-methylbutyl, 3-methylbutyl, and n-hexyl and isomers. In the subset of alkyl groups having 1 to 8 carbon atoms, particular examples are C 1-6 alkyl groups such as C 1-4 alkyl groups (e.g., C 1-3 alkyl groups or C 1-2 alkyl groups)

Examples of cycloalkyl groups are those derived from cyclopropane, cyclobutane, cyclopentane, cyclohexane and cycloheptane. In the subset of cycloalkyl groups, the cycloalkyl group will have from 3 to 8 carbon atoms, particular examples being the C 3-6 cycloalkyl groups.

Examples of alkenyl groups include, but are not limited to, ethenyl (vinyl), 1-propenyl, 2-propenyl (allyl), isopropenyl, butenyl, buta-1,4-dienyl, pentenyl and hexenyl. In the subset of alkenyl groups, the alkenyl group will have 2 to 8 carbon atoms, particular examples being C 2-6 alkenyl groups, such as C 2-4 alkenyl groups.

Examples of cycloalkenyl groups include, but are not limited to, cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclopentadienyl and cyclohexenyl. In the subset of cycloalkenyl groups, the cycloalkenyl groups have from 3 to 8 carbon atoms and the particular examples are the C 3-6 cycloalkenyl groups.

Examples of alkynyl groups include, but are not limited to, the ethynyl and 2-propynyl (propargyl) groups. In the subset of alkynyl groups having 2 to 8 carbon atoms, particular examples are C2-6 alkynyl groups, such as C2-4 alkynyl groups.

Examples of carbocyclic aryl groups include substituted and unsubstituted phenyl groups.

Examples of cycloalkylalkyl, cycloalkenylalkyl, carbocyclic aralkyl, aralkenyl and aralkynyl groups include the phenethyl, benzyl, styryl, phenylethynyl, cyclohexylmethyl, cyclopentylmethyl, cyclobutylmethyl, cyclopropylmethyl and cyclopentenylmethyl groups.

When present, and where specified, a hydrocarbyl group may be optionally substituted with one or more substituents selected from hydroxy, oxo, alkoxy, carboxyl, halogen, cyano, nitro, amino, mono- or di-C1-4 hydrocarbylamino, and carbocyclic groups and monocyclic or bicyclic heterocyclic groups having from 3 to 12 (typically 3 to 10 and more generally 5 to 10) ring members. Preferred substituents include halogens such as fluorine. Thus, for example, the substituted hydrocarbyl group may be a partially fluorinated or perfluorinated group such as difluoromethyl or trifluoromethyl. In one embodiment, preferred substituents include monocyclic carbocyclic and heterocyclic groups having 3-7 ring members, more generally 3, 4, 5 or 6 ring members.

Where specified, one or more carbon atoms of a hydrocarbyl group may be optionally substituted with O, S, SO, SO 2, NRC, X 1 C (X 2), C (X 2) X 1 or X 1 C (X 2) X 1 (or a subgroup thereof ) wherein X 1 and X 2 are as defined above, with the proviso that at least one carbon atom of the hydrocarbyl group remains. For example, 1, 2, 3 or 4 carbon atoms of the hydrocarbyl group may be substituted with one of the listed atoms or groups, and the substituent atoms or groups may be the same or different. In general, the number of linear carbon atoms or the skeleton substituted, will correspond to the number of linear atoms or the skeleton in the group that substitutes them. Examples of groups in which one or more carbon atoms of the hydrocarbyl group have been substituted with a substituent atom or group as defined above include ethers and thioethers (C substituted with O or S), amides, esters, thioamides and thioesters (CC substituted with X2C (X 2) or C (X 2) X 2), sulfones and sulfoxides (C substituted with SO or SO 2), amines (NRC substituted C). Other examples include the ureas, carbonates and carbamates (C 1 -C 4 -substituted C 1 -C 4) (X 2) X 1).

When an amino group has two hydrocarbyl substituents, they may be attached, together with the nitrogen atom to which they are attached, and optionally with another heteroatom such as nitrogen, sulfur or oxygen, to form a ring structure of 4 to 7 endocyclic members, more generally from 5 to 6 ring members. The term " aza-cycloalkyl " as used herein refers to a cycloalkyl group in which one of the carbon endocyclic members has been replaced with a nitrogen atom. Thus, examples of aza-cycloalkyl groups include piperidine and pyrrolidine. The term " oxa-cycloalkyl " as used herein refers to a cycloalkyl group wherein one of the carbon endocyclic members has been replaced with an oxygen atom. Thus, examples of oxa-cycloalkyl groups include tetrahydrofuran and tetrahydropyran. Similarly, the terms " diaza-cycloalkyl " " dioxa-cycloalkyl " and " aza-oxa-cycloalkyl " refer respectively to cycloalkyl groups in which two carbon endocyclic members have been substituted with two nitrogen atoms, or with two oxygen atoms, or with one nitrogen atom and one oxygen atom. The " Ra-Rb " as used herein, with respect to the substituents present a carbocyclic or heterocyclic moiety or with respect to other substituents present at other locations in the compounds of formula (II), includes inter alia compounds wherein Ra is selected from a bond, CO (O), SC (O), SC (NRc), NRcC (NRC), C (O) (NRC) 0, C (NRC) S, C (NRC) NRC, C (S) 0, C (S) S, C , 0C (0) 0, SC (0) 0, NRcC (0) 0, 0C (S) 0, SC (S) 0, NRCC (S) 0,0C (NRc) 0, SC (NRc) 0, NRcC (NRc) 0, 0C (0) S, SC (0) S, NRCC (0) S, 0C (S) S, SC (S) S, NRCC (S) S, ) NRcC (S) NRcC (S) NRcC (S) NRC, OC (NRC) NRC, NRC, NRC, NRC, , SC (NRc) NRc, NRcC (NRCNRC, S, SO, SO2, NRC, SO2 NRc and NRcS02 wherein Rc is as defined above The Rb moiety may be hydrogen or may be a group selected from carbocyclic and heterocyclic groups having from 3 to 12 endocyclic members (typically 3 to 10 and more generally from 5 to 10), and a C 1-8 hydrocarbyl group optionally substituted as defined above. Examples of hydrocarbyl, carbocyclic and heterocyclic groups are as indicated, above.

When Ra is O and Rb is a C1-8 hydrocarbyl group, Ra and Rb together form a hydrocarbyloxy group. Preferred hydrocarbyloxy groups include saturated hydrocarbyloxy such as alkoxy (eg, C1-6 alkoxy, more generally C1-4 alkoxy, such as ethoxy and methoxy, particularly methoxy), cycloalkoxy (eg, C3-6 cycloalkoxy such as cyclopropyloxy, cyclobutyloxy , cyclopentyloxy and cyclohexyloxy) and cycloalkylalkoxy (eg, C 3-6 cycloalkyl-C 1-2 alkoxy such as cyclopropylmethoxy).

The hydrocarbyloxy groups may be substituted with several substituents as defined herein. For example, the alkoxy groups may be substituted with halogen (eg, as in difluoromethoxy and trifluoromethoxy), hydroxy (eg as in hydroxyethoxy), C 1-2 alkoxy (eg as in methoxyethoxy), hydroxy-C 1-2 alkyl in hydroxyethoxyethoxy) or a cyclic group (eg, a cycloalkyl group or non-aromatic heterocyclic group as defined above). Examples of alkoxy groups having a non-aromatic heterocyclic group as a substituent are those in which the heterocyclic group is a saturated cyclic amine, such as morpholine, piperidine, pyrrolidine, piperazin, alkyl-C1-4-piperazines, cycloalkyl And the alkoxy group is a C1-4 alkoxy group, more typically a C1-3 alkoxy group, such as methoxy, ethoxy or n-propoxy.

Alkoxy groups substituted with a monocyclic group, such as pyrrolidine, piperidine, morpholine and piperazine and their N-substituted derivatives, such as N-benzyl, N-C1-4-acyl and N-C1-4-alkoxycarbonyl. Particular examples include pyrrolidinoethoxy, piperidinoethoxy and piperazinoethoxy.

When Ra is a bond and Rb is a C1-8 hydrocarbyl group, examples of the hydrocarbyl group Ra-Rb are as defined above. The hydrocarbyl groups may be saturated groups such as cycloalkyl and alkyl and particular examples of such groups include methyl, ethyl and cyclopropyl. The hydrocarbyl (e.g., alkyl) groups may be substituted with various groups and atoms as defined herein. Examples of substituted alkyl groups include alkyl groups substituted with one or more halogen atoms, such as fluorine and chlorine (including particular examples bromoethyl, chloroethyl and trifluoromethyl), or hydroxyl (eg, hydroxymethyl and hydroxyethyl), C 1-8 acyloxy , acetoxymethyl and benzyloxymethyl), amino and mono- and dialkylamino (eg, aminoethyl, methylaminoethyl, dimethylaminomethyl, dimethylaminoethyl and tert-butylaminomethyl), alkoxy (eg, C 1-2 alkoxy such as methoxy and methoxyethyl) and cyclic groups such as cycloalkyl groups, aryl groups, heteroaryl groups and non-aromatic heterocyclic groups as defined above).

Particular examples of cyclic substituted alkyl groups are those in which the cyclic group is a saturated cyclic amine, such as morpholine, piperidine, pyrrolidine, piperazin, alkyl-C1-4-piperazines, C3- 7-piperazines, tetrahydropyran or tetrahydrofuran and the alkyl group is a C1-4 alkyl group, more typically a C1-3 alkyl group such as methyl, ethyl or n-propyl. Specific examples of alkyl groups substituted with a cyclic group include pyrrolidinomethyl, pyrrolidinopropyl, morpholinomethyl, morpholinoethyl, morpholinopropyl, piperidinylmethyl, piperazinomethyl and N-substituted forms thereof as defined herein.

Particular examples of alkyl groups substituted with aryl groups and heteroaryl groups include benzyl and pyridylmethyl groups.

When Ra is SO2 NRC, Rb may be, for example, hydrogen or an optionally substituted C1-8 hydrocarbyl group, or a carbocyclic or heterocyclic group. Examples of Ra-Rb where Ra is SO2 NRc include the aminosulfonyl, C1-4 alkylaminosulphonyl and di-C1-4 alkylaminosulphonyl groups, and sulfonamides formed from a cyclic amino group such as piperidine, morpholine, pyrrolidine, or an optionally N-substituted piperazine such as N-methylpiperazine.

Examples of Ra-Rb groups wherein Ra is SO2 include the alkylsulfonyl, heteroarylsulfonyl and arylsulfonyl groups, in particular monocyclic aryl and heteroarylsulfonyl groups. Particular examples include methylsulfonyl, phenylsulfonyl and toluenesulfonyl.

When Ra is NRC, Rb may be, for example, hydrogen or an optionally substituted C1-8 hydrocarbyl group, or a carbocyclic or heterocyclic group. Examples of Ra-Rb wherein Ra is NRC include amino, C1-4-alkylamino (eg, methylamino, ethylamino, propylamino, isopropylamino, tert-butylamino), di-C1-4-alkylamino (eg dimethylamino and diethylamino) and cycloalkylamino (eg, cyclopropylamino, cyclopentylamino and cyclohexylamino).

Specific Embodiments and Preferences for Y, R1 to R3 and R10 R2 is hydrogen or methyl, most preferably hydrogen. R 1 is a carbocyclic or heterocyclic group having from 3 to 12 ring members, wherein the carbocyclic or heterocyclic group is unsubstituted or substituted with one or more substituent groups R 10, or a C 1-8 hydrocarbyl group optionally substituted with one or more substituents (eg fluorine), hydroxy, C1-4 hydrocarbyloxy, amino, C1-4 mono- or dihydrocarbylamino, and carbocyclic or heterocyclic groups having from 3 to 12 ring members, wherein the carbocyclic or heterocyclic group is not substituted or substituted with one or more substituent groups R 10, and wherein 1 or 2 of the carbon atoms of the hydrocarbyl group may be optionally substituted with one atom or group selected from O, S, NH, SO, SO 2. Examples of carbocyclic or heterocyclic groups and hydrocarbyl groups and the general preferences for such groups are as indicated above in the General Preferences and Definitions section, and as specified below.

In one embodiment, R 1 is an aryl or heteroaryl group.

When R 1 is a heteroaryl group, particular heteroaryl groups include monocyclic heteroaryl groups containing up to three heteroatom heteroatom members selected from O, S and N, and bicyclic heteroaryl groups containing up to 2 heteroatom ring members selected from O, S and N and in that both rings are aromatic.

Examples of such groups include furanyl (eg, 2-furanyl or 3-furanyl), indolyl (eg, 3-indolyl, 6-indolyl), 2,3-dihydro-benzo [1,4] dioxinyl (eg, 2- , 3-dihydro-benzo [1,4] dioxin-5-yl), pyrazolyl (eg, pyrazole-5-yl), pyrazolo [1,5- a] pyridinyl (eg, pyrazolo [1,5- a (eg, 2-pyridyl, 3-pyridyl, 4-pyridyl), quinolinyl (eg, 2-quinolinyl), pyridyl (eg, 2-pyridyl) pyrrolyl (eg, 3-pyrrolyl), imidazolyl and thienyl (eg, 2-thienyl, 3-thienyl).

A subgroup of heteroaryl groups R 1 consists of furanyl (e.g., 2-furanyl or 3-furanyl), indolyl, oxazolyl, isoxazolyl, pyridyl, quinolinyl, pyrrolyl, imidazolyl and thienyl.

A preferred subset of heteroaryl groups R 1 includes 2-furanyl, 3-furanyl, pyrrolyl, imidazolyl and thienyl.

Preferred aryl groups R1 are phenyl groups. The group R 1 may be an unsubstituted or substituted carbocyclic or heterocyclic group wherein one or more substituents may be selected from the group R 10 as defined above. In one embodiment, the substituents on R1 may be selected from the group R10a consisting of halogen, hydroxy, trifluoromethyl, cyano, nitro, carboxyl, a group Ra-Rb wherein Ra is a bond, O, CO, X3C (X4) , R 2 is selected from hydrogen and a C 1 -C 8 hydrocarbyl group optionally substituted with one or more substituents selected from hydroxy, oxo, halogen, cyano, nitro, C 1 -C 4 -alkoxy, , carboxy and non-aromatic monocyclic carbocyclic or heterocyclic groups having from 3 to 6 ring members; wherein one or more carbon atoms of the C1-8 hydrocarbyl group may be optionally substituted with O, S, SO, SO2, X3 C (X4), C (X4) X3 or X3 C (X4) X3; X3 is O or S; and X4 is = O or = S.

When the carbocyclic and heterocyclic groups have a pair of substituents on adjacent ring atoms, the two substituents may be attached to form a cyclic group. Thus, two adjacent R 10 groups together with the carbon atoms or heteroatoms to which they are attached may form a 5-membered heteroaryl ring or a 5- or 6-membered non-aromatic carbocyclic or heterocyclic ring, wherein said heteroaryl and heterocyclic rings contain up to 3 heteroatom ring members selected from N, O and S. In particular, the two adjacent R 10 groups together with the carbon atoms or heteroatoms to which they are attached may form a 6-membered non-aromatic heterocyclic ring, containing up to 3, in particular 2, heteroatom ring members selected from N, O and S. More particularly, the two adjacent R 10 groups may form a 6-membered non-aromatic heterocyclic ring containing 2 heteroatom endocyclic members selected from N, or 0, such as dioxane, e.g. g., [1,4-dioxane]. In one embodiment, R1 is a carbocyclic group, e.g. phenyl having a pair of substituents on adjacent endocyclic atoms attached to form a cyclic group, e.g. to form 2,3-dihydro-benzo [1,4] dioxin.

More particularly, the substituents on R 1 may be selected from halogen, hydroxy, trifluoromethyl, a Ra 1 R 2 group wherein R 1 is a bond or O, and R b is selected from hydrogen and a C 1-4 hydrocarbyl group optionally substituted with one or more substituents selected from hydroxyl, halogen (preferably fluorine) and saturated 5- and 6-membered carbocyclic and heterocyclic groups (for example, groups containing up to two heteroatoms selected from O, N, such as piperidine, pyrrolidino, morpholino, piperazino and N-methylpiperazine not replaced). The R1 group may be substituted with more than one substituent. Thus, for example, there may be 1 or 2 or 3 or 4 substituents. In one embodiment, when R 1 is a six membered ring (eg, a carbocyclic ring such as a phenyl ring), one, two or three substituents may exist and these may be located at the 2, 3, 4, or 6 positions around of the ring. By way of example, a phenyl group R 1 may be 2-monosubstituted, 3-monosubstituted, 2,6-disubstituted, 2,3-disubstituted, 2,4-disubstituted 2,5-disubstituted, 2,3,6-trisubstituted or 2, 4,6-trisubstituted. More particularly, a phenyl group R 1 may be mono-substituted at the 2-position or disubstituted at the 2 and 6-positions with substituents selected from fluorine, chlorine and Ra-Rb, wherein R a is 0 and R b is C 1-4 alkyl (eg, methyl or ethyl ). In one embodiment, fluorine is a preferred substituent. In another embodiment, the preferred substituents are selected from fluorine, chlorine and methoxy.

Particular examples of non-aromatic R1 groups include unsubstituted or substituted monocyclic cycloalkyl groups (with one or more R10 groups). Examples of such cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl; more typically cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl, particularly cyclohexyl.

Further examples of non-aromatic R1 groups include heterocyclic groups having from 3 to 12 ring members, typically 4 to 12 ring members, and more generally from 5 to 10 ring members, unsubstituted or substituted (with one or more R10 groups). Such groups may be, for example, monocyclic or bicyclic and typically have from 1 to 5 heteroatom (more generally 1, 2, 3 or 4 heteroatom) ring members typically selected from nitrogen, oxygen and sulfur.

When sulfur is present, it may exist as -S-, -S (O) - or -S (O) 2 - r when the nature of adjacent atoms and groups permits.

The heterocyclic groups may contain, for example, cyclic ether units (eg as in tetrahydrofuran and dioxane), cyclic thioether units (eg, as in tetrahydrothiophene and dithiane), cyclic amine units (eg as in pyrrolidine (eg as in butyrolactone), cyclic thioamides and thioesters, cyclic sulfones (eg as in sulfolane and sulfolene), cyclic sulfoxides, cyclic sulfonamides and their combinations (eg, morpholine and thiomorpholine and their S-oxide and S, S-dioxide).

In a subset of heterocyclic groups R1, heterocyclic groups contain cyclic ether units (eg as in tetrahydrofuran and dioxane), cyclic thioether units (eg, as in tetrahydrothiophene and dithiane), cyclic amine units (eg as in pyrrolidine ), cyclic sulfones (eg as in sulfolane and sulfolene), cyclic sulfoxides, cyclic sulfonamides and their combinations (eg, thiomorpholine).

Examples of non-aromatic monocyclic heterocyclic groups R 1 include 5-, 6- and 7-membered monocyclic heterocyclic groups such as morpholine, piperidine (eg, 1-piperidinyl, 2-piperidinyl 3-piperidinyl and 4-piperidinyl), pyrrolidine (eg, 1 pyrrolidinyl, 2-pyrrolidinyl and 3-pyrrolidinyl), pyrrolidone, pyran (2H-pyran or 4H-pyran), dihydrothiophene, dihydropyran, dihydrofuran, dihydrothiazole, tetrahydrofuran, tetrahydrothiophene, dioxane , tetrahydropyran (eg, 4-tetrahydropyranyl), imidazoline, imidazolidinone, oxazoline, thiazoline, 2-pyrazoline, pyrazolidine, piperazine and N-alkylpiperazines such as N-methylpiperazine. Further examples include thiomorpholine and its S-oxide and S, S-dioxide (particularly thiomorpholine). Still other examples include N-alkylpiperidines such as N-methylpiperidine.

A subgroup of non-aromatic heterocyclic groups R 1 includes unsubstituted or substituted monocyclic 5-, 6- and 7-membered heterocyclic groups (with one or more R 10 groups) such as morpholine, piperidine (eg, 1-piperidinyl, 2-piperidinyl 3-piperidinyl and 4-piperidinyl), pyrrolidine (eg, 1-pyrrolidinyl, 2-pyrrolidinyl and 3-pyrrolidinyl), pyrrolidone, piperazine and N-alkylpiperazines such as N-methylpiperazine, wherein a particular subset consists of pyrrolidine, piperidine, morpholine, thiomorpholine and N-methylpiperazine.

In general, preferred non-aromatic heterocyclic groups include pyrrolidine, piperidine, morpholine, thiomorpholine, S, S-thiomorpholine dioxide, piperazine, N-alkylpiperazines and N-alkylpiperidines.

Another particular subset of heterocyclic groups consists of pyrrolidine, piperidine, morpholine and N-alkylpiperazines and, optionally, N-methylpiperazine and thiomorpholine.

When R 1 is a C 1-8 hydrocarbyl group substituted with a carbocyclic or heterocyclic group, the carbocyclic and heterocyclic groups may be aromatic or non-aromatic and may be selected from the examples of such groups indicated above. The substituted hydrocarbyl group is typically a saturated C 1-4 hydrocarbyl group such as an alkyl group, preferably a CH 2 or CH 2 CH 2 group. When the substituted hydrocarbyl group is a C 2-4 hydrocarbyl group, one of the carbon atoms and their associated hydrogen atoms may be substituted with a sulfonyl group, for example as in the SO 2 CH 2 moiety.

When the carbocyclic or heterocyclic group attached to a C1-8 hydrocarbyl group is aromatic, examples of such groups include monocyclic aryl groups and monocyclic heteroaryl groups containing up to four heteroatom endocyclic heteroatoms selected from O, S and N, and bicyclic heteroaryl groups containing up to 2 heteroatom ring members selected from O, S and N and wherein both rings are aromatic.

Examples of such groups are indicated in the " General Preferences & Definitions " above.

Particular examples of such groups include furanyl (e.g., 2-furanyl or 3-furanyl), indolyl, oxazolyl, isoxazolyl, pyridyl, quinolinyl, pyrrolyl, imidazolyl and thienyl. Particular examples of aryl and heteroaryl groups as substituents for a C1-8 hydrocarbyl group include phenyl, imidazolyl, tetrazolyl, triazolyl, indolyl, 2-furanyl, 3-furanyl, pyrrolyl and thienyl. Such groups may be substituted with one or more substituents R 10 or R 10a as defined herein.

When R 1 is a C 1-8 hydrocarbyl group substituted with a non-aromatic carbocyclic or heterocyclic group, the heterocyclic or non-aromatic group may be a group selected from the lists of such groups indicated above. For example, the non-aromatic group may be a monocyclic group having from 4 to 7 ring members, e.g. 5 to 7 ring members, and typically containing from 0 to 3, more typically 0, 1 or 2, heteroatom ring members selected from O, Si N. When the cyclic group is a carbocyclic group, it may be further selected of monocyclic groups having 3 endocyclic members. Particular examples include monocyclic cycloalkyl groups such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl, and 5-, 6- and 7-membered monocyclic heterocyclic groups such as morpholine, piperidine (eg, 1-piperidinyl, 2- piperidinyl, 3-piperidinyl and 4-piperidinyl), pyrrolidine (eg, 1-pyrrolidinyl, 2-pyrrolidinyl and 3-pyrrolidinyl), pyrrolidone, piperazine and N-alkylpiperazines such as N-methylpiperazine. In general, preferred non-aromatic heterocyclic groups include pyrrolidine, piperidine, morpholine, thiomorpholine and N-methylpiperazine.

When R1 is an optionally substituted C1-8 hydrocarbyl group, the hydrocarbyl group may be as defined above, and is preferably up to four carbon atoms in length, more generally up to three carbon atoms in length, for example , one or two carbon atoms in length.

In one embodiment, the hydrocarbyl group is saturated and may be acyclic or cyclic, for example, acyclic. An acyclic saturated hydrocarbyl group (i.e., an alkyl group) may be a straight or branched chain alkyl group.

Examples of R 1 linear chain alkyl groups include methyl, ethyl, propyl and butyl.

Examples of branched-chain alkyl groups R 1 include isopropyl, isobutyl, tert -butyl and 2,2-dimethylpropyl.

In one embodiment, the hydrocarbyl group is a linear saturated group having from 1-6 carbon atoms, more generally 1-4 carbon atoms, e.g., 1-3 carbon atoms, e.g. 1, 2 or 3 carbon atoms. When the hydrocarbyl group is substituted, particular examples of such groups are substituted methyl and ethyl groups (e.g., with a carbocyclic or heterocyclic group).

A C1-4 hydrocarbyl group may be optionally substituted with one or more substituents selected from halogen (egr fluoro), hydroxy, C1-4 hydrocarbyloxy, amino, C1-4 mono- or dihydrocarbylamino, and carbocyclic or heterocyclic groups having from 3 to 12 ring members, and wherein 1 or 2 carbon atoms of the hydrocarbyl group may be optionally substituted with one atom or group selected from O, S, NH, SO, SO 2. Particular substituents for the hydrocarbyl group include hydroxyl, chlorine, fluorine (e.g., as in trifluoromethyl), methoxy, ethoxy, amino, methylamino and dimethylamino, the preferred substituents being hydroxy and fluoro.

Particular R1-CO groups are the groups shown in Table 1 below.

In Table 1, the point of attachment of the group to the nitrogen atom of the pyrazole-4-amino group is represented by the terminal single bond extending from the carbonyl group. Thus, by way of illustration, the group B in the table is the trifluoroacetyl group, the D group in the table is the phenylacetyl group and the group I in the table is the 3- (4-chlorophenyl) propionyl group.

A subgroup of R1-CO groups consists of the groups A through BF in Table 1 above.

Another subgroup of R1-CO groups consists of groups A to BS in Table 1 above.

A group of preferred R1-CO groups consists of the groups J, AB, AH, AJ, AL, AS, AX, AY, AZ, BA, BB, BD, BH, BL, BQ, BS and BAI

Another set of preferred R1-CO groups consists of the groups J, AB, AH, AJ, AL, AS, AX, AY, AZ, BA, BB, BD, BH, BL, BQ and BS.

More preferred R1-CO groups are AJ, AX, BQ, BS and BAI.

A particularly preferred subset of R1-CO-groups consists of AJ, BQ and BS.

Another particularly preferred subset of R1-CO-groups consists of AJ and BQ.

When R1 is a phenyl ring having a 4-position substituent, the 4-position substituent is preferably different from a phenyl group having a SO2 NH2 or SO2 Me group in the ortho position.

In a general embodiment, R1 may be different from a substituted or unsubstituted tetrahydroquinoline, chroman, chromene, thiochroman, thiochromene, dihydro-naphthalene or tetrahydronaphthalene group. More particularly, R1 may be other than a tetrahydroquinoline, chroman, chromene, thiochroman, thiochromene, dihydro-naphthalene or tetrahydronaphthalene group attached by its aromatic ring to the substituted or unsubstituted A-NR4- moiety.

In another general embodiment, when R 1 is a substituted or unsubstituted phenyl group, the Y-R 3 moiety may be other than unsubstituted C 5-10 cycloalkyl.

When R1 is an optionally substituted hydrocarbyl group and the hydrocarbyl group comprises or contains a substituted or unsubstituted alkene group, it is preferred that the carbon-carbon double bond of the alkene group is not directly attached to the group A.

When R1 is an optionally substituted hydrocarbyl group, the hydrocarbyl group may be different from an alkene group.

Y

In the compounds of formula (II), Y is a bond or an alkylene chain of 1, 2 or 3 carbon atoms in length. The term " alkylene " has its usual meaning and refers to a bivalent chain of acyclic saturated hydrocarbon. The hydrocarbon chain may be branched or unbranched. When an alkylene chain is branched, it may have one or more methyl group side chains. Examples of alkylene groups include -CH 2 -, -CH 2 -CH 2 -, -CH 2 -CH 2 -CH 2 -, CH (CH 3) -, -C (CH 3) 2, -CH 2 -CH (CH 3) -CH 2 -C ) 2 and -CH (CH 3) -CH (CH 3)

In one embodiment, Y is a bond.

In another embodiment, Y is an alkylene chain.

When Y is an alkylene chain, it is preferably unbranched and more particularly contains 1 or 2 carbon atoms, preferably 1 carbon atom. Thus, preferred groups Y are -CH 2 - and -CH 2 -CH 2 -, a most preferred group being (CH 2) -.

When Y is a branched chain, it preferably has no more than two methyl side chains. For example, it may have a single methyl side chain. In one embodiment, Y is a -CH (Me) - group.

In a subgroup of compounds, Y is a bond, CH2, CH2CH2 or CH2CH (CH3).

The group R 3 is selected from non-aromatic carbocyclic and heterocyclic groups having from 3 to 12 endocyclic members.

In another subgroup of compounds, Y is a bond or an alkylene chain (e.g., a - (CH2) -) group and R3 is a non-aromatic carbocyclic or heterocyclic group.

In another subset of compounds, Y is a bond and R 3 is a non-aromatic carbocyclic or heterocyclic group.

In yet another subset of compounds, Y is an alkylene chain (e.g., a - (CH2) -) group and R3 is a non-aromatic carbocyclic or heterocyclic group.

The carbocyclic and heterocyclic R 3 groups may be non-aromatic carbocyclic or non-aromatic heterocyclic and examples of such groups are as detailed in above in the General Preferences and Definitions section, and as indicated below.

Examples of non-aromatic R 3 groups include the optionally substituted cycloalkyl, oxa-cycloalkyl, aza-cycloalkyl, diaza-cycloalkyl, dioxa-cycloalkyl and aza-oxa-cycloalkyl groups (with R 10 or R 10a). Other examples include the C7-10 aza-bicycloalkyl groups such as 1-aza-bicyclo [2.2.2] octan-3-yl.

Particular examples of such groups include the unsubstituted or substituted cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, tetrahydropyran, morpholine, tetrahydrofuran, piperidine and pyrrolidine groups.

A subset of non-aromatic R 3 groups consists of the cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, tetrahydropyran, tetrahydrofuran, piperidine and pyrrolidine groups.

Preferred non-aromatic R 3 groups include the unsubstituted or substituted cyclopentyl, cyclohexyl, tetrahydropyran, tetrahydrofuran, piperidine and pyrrolidine groups.

The non-aromatic groups may be unsubstituted or substituted with one or more R 10 or R 10a groups as defined above.

Particular substituents for R 3 are selected from the group R 10a consisting of halogen; hydroxy; monocyclic carbocyclic and heterocyclic groups having from 3 to 6 ring members and containing up to 2 heteroatom ring members selected from O, Ne S; and a Ra-Rb group wherein Ra is a bond, CO, CO 2, SO 2, NH, SO 2 NH, or NHSO 2; and Rb is selected from hydrogen, a 3-6 membered carbocyclic or heterocyclic ring containing up to 2 heteroatom ring members selected from O, N and S; and a C1-6 hydrocarbyl group optionally substituted with one or more substituents selected from hydroxyl, oxo, halogen, carboxyl, amino, C1-4 mono- or dihydrocarbylamino, a 3-6 membered heterocyclic and heterocyclic ring containing up to 2 heteroatom endocyclic members selected from O, N and S; and wherein one or two carbon atoms of the C 1-6 hydrocarbyl group may be optionally substituted with O, S, SO, SO 2 or NH.

In one embodiment, preferred R10a substituent groups in R3 include halogen, a Ra-Rb group wherein Ra is a bond, O, CO, C (X2) X1, and Rb is selected from hydrogen, heterocyclic groups having 3-7 and a C1-4 hydrocarbyl group optionally substituted with one or more substituents selected from hydroxyl, carboxy, amino, C1-4 mono- or dihydrocarbylamino, and heterocyclic groups having 3-7 endocyclic members.

Particularly preferred R10a groups in R3 include halogen, especially fluorine, C1-3 alkoxy such as methoxy, and C1-3 hydrocarbyl optionally substituted with fluorine, hydroxyl (eg, hydroxymethyl), C1-2 alkoxy or a saturated heterocyclic ring of 5 or 6 members, such as piperidino, morpholino, piperazino and N-methylpiperazino.

In another embodiment, the substituents for R 3 are selected from: • halogen (eg, fluorine and chlorine) • C 1-4 alkoxy (eg, methoxy and ethoxy) optionally substituted with one or substituents selected from halogen, hydroxy, C 1-2 alkoxy and saturated five- and six-membered heterocyclic rings containing 1 or 2 heteroatoms selected from O, NeS, the heterocyclic rings being optionally substituted with one or more C1-4 groups (eg, methyl) and wherein the S, when present, may be present as S, SO or SO2; C1-4 alkyl optionally substituted with one or substituents selected from halogen, hydroxy, C1-4 alkoxy, amino, C1-4 alkylsulfonylamino, 3-6 membered cycloalkyl groups (eg, cyclopropyl), phenyl (optionally substituted with one or more substituents selected from halogen, methyl, methoxy and amino) and saturated five- and six-membered heterocyclic rings containing 1 or 2 heteroatoms selected from O, N and S, the heterocyclic rings being optionally further substituted with one or more C1- 4 (eg, methyl) and wherein the S, when present, may be present as S, SO or SO 2; • hydroxyl; Amino, mono-C1-4-alkylamino, di-C1-4-alkylamino, benzyloxycarbonylamino and C1-4-alkoxycarbonylamino; • carboxy and C1-4 alkoxycarbonyl; • C1-4 alkylaminosulfonyl and C1-4 alkylsulfonylamino; • C1-4 alkylsulfonyl; • a 0-Hets or NH-Hets group wherein Hets is a five- or six-membered saturated heterocyclic ring containing 1 or 2 heteroatoms selected from O, NeS, the heterocyclic rings being optionally substituted with one or more C1-4 groups (eg, methyl) and wherein the S, when present, may be present as S, SO or SO2; Five- and six-membered saturated heterocyclic rings containing 1 or 2 heteroatoms selected from O, NeS, the heterocyclic rings being optionally substituted with one or more C1-4 groups (eg, methyl) and wherein the S, when present, may be present as S, SO or SO2; • oxo; and • six membered aryl and heteroaryl rings containing up to two endocyclic nitrogen members and being optionally substituted with one or substituents selected from halogen, methyl and methoxy.

In another embodiment, R 3 is selected from: C 3 -C 7 cycloalkyl groups optionally substituted with 1-4 (e.g., 1-2, e.g., 1) substituents R 10 or R 10a; Five-membered saturated heterocyclic rings containing 1-endocyclic heteroatom selected from O, N and S and being optionally substituted with an oxo group and / or with 1-4 (e.g. 1-2, eg, 1) substituents R10 or R10a ; Saturated six membered heterocyclic rings containing 1 or 2 ring heteroatoms selected from O, N and S and optionally substituted with an oxo group and / or with 1-4 (e.g. 1-2, eg, 1) substituents R10 or R10a; • mono-azabicycloalkyl and diazabicycloalkyl groups each having 7 to 9 ring members and being optionally substituted with 1-4 (e.g., 1-2, e.g., 1) substituents R10 or R10a.

Specific examples of the group Y-R 3 are indicated in

In Table 2, the point of attachment of the group to the nitrogen atom of the pyrazole-3-carboxamide group is represented by the terminal single bond extending from the group.

A subset of groups selected from Table 2 consists of groups CA to EU.

Another subset of groups selected from Table 2 consists of groups CA to CV.

Preferred groups selected from Table 2 include the CL, CM, ES, ET and FC groups.

Particularly preferred groups selected from Table 2 include the CL, CM and ES groups, and most preferably the CL and CM groups.

When R 3 is an aza-cycloalkyl group, the nitrogen atom of the aza-cycloalkyl group is preferably unsubstituted with an alkylene chain attached to a 2,3-dihydro-benzo [1,4] dioxine group or tetra -hydronaphthalene.

In another general embodiment, R 3 is other than a unit containing a five membered heteroaryl ring attached directly by a single bond to a monocyclic or bicyclic aryl group or R 3 is other than a bis heteroaryl group containing unit comprising two heteroaryl rings of five members linked together by a simple link.

In another general embodiment, R1 is other than a unit containing a five membered heteroaryl ring attached directly by a single bond to a monocyclic or bicyclic aryl group or R1 is other than a bis heteroaryl group containing unit comprising two heteroaryl rings of five members linked together by a single link.

In another general embodiment, R 1 - (CO) -NH is other than an optionally substituted nicotinoylamino or benzoylamino group when Y-R 3 is an optionally substituted alkyl, cycloalkyl, phenyl, or phenylalkyl group.

In one embodiment, Y-R 3 may be different from a cycloalkyl group substituted at the 1-position with a hydrocarbon chain having both an oxy substituent such as hydroxyl, an aryl substituent and a diazole or triazole substituent.

Preferably, R 1 or R 3 are each different from a substituted phenyl group-containing moiety having thio and / or oxy substituents such as hydroxyl, alkoxy and alkylthio at both the 3- and 4-positions of the phenyl ring.

Preferably, the group Y-R 3 does not include a lactam moiety fused with benzene having attached thereto an unsubstituted or substituted imidazole group.

Preferably, the group Y-R 3 does not include the -CH = C-unit (CC > 2Rq) -S- wherein R ' is hydrogen or alkyl.

In another general embodiment, neither of R 1 or R 3 contains a moiety in which a five-membered nitrogen-containing heteroaryl group is attached directly or via an alkylene, oxa-alkylene, thien-alkylene or aza-alkylene group to an unsubstituted pyridyl group or to a substituted aryl, heteroaryl or piperidine ring, each of said rings having attached thereto a substituent selected from cyano, and substituted or unsubstituted amino, aminoalkyl, amidine, guanidine and carbamoyl groups.

In another general embodiment, R 1 and R 3 are each different from an unsaturated nitrogen-containing heterocyclic group, or a benzofuran or benzothiophene group wherein said nitrogen-containing heterocyclic group, nitrogen-containing heteroaryl group, benzofuran or benzothiophene bicyclic group are linked directly by a single bond to a pyridyl or substituted phenyl group.

In another general embodiment, neither of R 1 or R 3 contains a moiety in which a five-membered nitrogen-containing heteroaryl group is attached directly or via an alkylene, oxa-alkylene, thien-alkylene or aza-alkylene group to an aryl, heteroaryl or substituted piperidine or an unsubstituted pyridyl group.

In general, it is preferred that the compounds of the invention, when containing a carboxylic acid group, have not more than one such group.

Particular and Preferred Subgroups of Formulas (II)

The compounds of formula (II) are represented by formula (II):

or salts or tautomers or N-oxides or solvates thereof; wherein R 1, R 2, R 3 and Y are each independently selected from R 1, R 2, R 3 and Y as defined herein.

In formula (II) it is preferred that R 2 is hydrogen or C 1-4 alkyl (e.g., C 1-3 alkyl), and more preferably R 2 is hydrogen.

In a subgroup of compounds of formula (II), R1 is: (i) phenyl optionally substituted with one or more substituents (e.g., 1, 2 or 3) selected from fluoro; chloro; hydroxy; saturated 5- and 6-membered heterocyclic groups containing 1 or 2 heteroatoms selected from O, N and S, the heterocyclic groups being optionally substituted with one or more C 1-4 alkyl groups; C1-4 hydrocarbyloxy; and C 1-4 hydrocarbyl; wherein the C 1-4 hydrocarbyl and C 1-4 hydrocarbyloxy groups are optionally substituted with one or more substituents selected from hydroxy, fluoro, C 1-2 alkoxy, amino, mono and di-C 1-4 alkylamino, phenyl, halophenyl, saturated carbocyclic rings having 3 to 7 ring members (more preferably 4, 5 or 6 ring members, eg 5 or 6 ring members) or 5- to 6-membered saturated heterocyclic ring groups containing up to 2 heteroatoms selected from O, S N; or 2,3-dihydro-benzo [1,4] dioxine; or (ii) a monocyclic heteroaryl group containing one or two heteroatoms selected from O, Si N; or a bicyclic heteroaryl group containing a single heteroatom selected from O, Si N; each of the monocyclic and bicyclic heteroaryl groups being optionally substituted with one or more substituents selected from fluoro; chloro; C1-3 hydrocarbyloxy; and C1-3 hydrocarbyl optionally substituted with hydroxy, fluoro, methoxy or a five- or six-membered saturated carbocyclic or heterocyclic group containing up to two heteroatoms selected from O, S and N; or (iii) a substituted or unsubstituted cycloalkyl group having from 3 to 6 ring members; or (iv) a C1-4 hydrocarbyl group optionally substituted with one or more substituents selected from fluoro; hydroxy; C1-4 hydrocarbyloxy; amino; C1-4 mono- or dihydrocarbylamino; and carbocyclic or heterocyclic groups having from 3 to 12 ring members, and wherein one of the carbon atoms of the hydrocarbyl group may be optionally substituted with one atom or group selected from O, NH, SO and SO2.

In group (i), a subgroup of R1 groups consists of phenyl optionally substituted with one or more substituents selected from fluoro; chloro; hydroxy; C1-3 hydrocarbyloxy; and C1-3 hydrocarbyl wherein the C1-3 hydrocarbyl group is optionally substituted with one or more substituents selected from hydroxy, fluoro, C1-2 alkoxy, amino, mono and di-C1-4-alkylamino, saturated carbocyclic groups having 3 to 7-membered endocyclic (more preferably 4-, 5- or 6-membered endocyclic, eg 5- or 6-membered endocyclic members) or 5- to 6-membered saturated heterocyclic groups containing up to 2 heteroatoms selected from O, S and N.

In another subgroup of compounds of formula (II), R1 is selected from (i) and (iii) above and in addition to a subset (aii) wherein the subset (aii) consists of 2-furanyl, 3-furanyl, imidazolyl, 2- indolyl, 2-thienyl and 3-thienyl, each optionally substituted with one or more substituents selected from fluoro, chloro, C1-3 hydrocarbyloxy and C1-3 hydrocarbyl optionally substituted with hydroxy, fluoro or methoxy.

In the group of compounds defined by formula (II), wherein R 1 is (i) an optionally substituted phenyl group, this may be, for example, an unsubstituted phenyl group or a 2-monosubstituted, 3-monosubstituted, 3-disubstituted, 2,5-disubstituted or 2,6-disubstituted or 2,3-dihydro-benzo [1,4] dioxine, wherein the substituents are selected from halogen; hydroxy; C1-3 alkoxy; and C 1-3 alkyl groups wherein the C 1-3 alkyl group is optionally substituted with hydroxy, fluoro, C 1-2 alkoxy, amino, mono and di-C 1-4 alkylamino, or saturated carbocyclic groups having 3 to 6 ring members and / or saturated 5- or 6-membered heterocyclic ring groups containing 1 or 2 heteroatoms selected from N and O.

In one embodiment, R1 is selected from unsubstituted phenyl, 2-fluorophenyl, 2-hydroxyphenyl, 2-methoxyphenyl, 2-methylphenyl, 2- (2- (pyrrolidin-1-yl) ethoxy) -phenyl, 3-fluorophenyl, 3-methoxyphenyl, 2,6-difluorophenyl, 2-fluoro-6-hydroxyphenyl, 2-fluoro-3-methoxyphenyl, 2-fluoro-5-methoxyphenyl, 2-chloro-6-methoxyphenyl, 2-fluoro- 2,6-dichlorophenyl and 2-chloro-6-fluorophenyl, and is further optionally selected from 5-fluoro-2-methoxyphenyl.

In another embodiment, R1 is selected from unsubstituted phenyl, 2-fluorophenyl, 2-hydroxyphenyl, 2-methoxyphenyl, 2-methylphenyl, 2- (2- (pyrrolidin-1-yl) ethoxy) -phenyl, 3-fluorophenyl, 3-methoxyphenyl, 2,6-difluorophenyl, 2-fluoro-6-hydroxyphenyl, 2-fluoro-3-methoxyphenyl and 2-fluoro-5-methoxyphenyl.

Particular R1 groups are 2,6-difluorophenyl, 2-fluoro-6-methoxyphenyl and 2,6-dichlorophenyl.

A particularly preferred R1 group is 2,6-difluorophenyl.

Another particularly preferred R1 group is 2,6-dichlorophenyl.

When R1 is (ii) a monocyclic heteroaryl group containing one or two heteroatoms selected from O, S and N or a bicyclic heteroaryl group containing a single heteroatom, examples of monocyclic and bicyclic heteroaryl groups include furanyl groups (eg, 2-furanyl and 3-furanyl), imidazolyl, pyridyl (eg, 2-pyridyl), indolyl, thienyl (eg, 2-thienyl and 3-thienyl). Optional substituents for such groups may include chloro, fluoro, methyl, methoxy, hydroxymethyl, methoxymethyl, morpholinomethyl, piperazinomethyl, N-methylpiperazinomethyl and piperidinylmethyl groups. Particular examples of groups (ii) include unsubstituted 2-furanyl, 3-methyl-2-furanyl, unsubstituted 4- (1H) -imidazolyl, unsubstituted 5- (1H) -imidazolyl, unsubstituted 3-furanyl, 3- 2-methyl-3-thienyl and unsubstituted 3-pyrrolyl, and other examples include the 4-methoxy-3-thienyl, 5- (1-pyrrolidinyl) methyl-2-furyl and 5- (4 morpholino) methyl-2-furyl.

When R1 is (iii) an optionally substituted cycloalkyl group, this may be, for example, a substituted or unsubstituted cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl group. When the cycloalkyl group is substituted, preferred substituents include methyl, fluoro and hydroxyl. Particular examples of cycloalkyl groups include unsubstituted 1-methylcyclopropyl, 1-hydroxycyclopropyl, and cyclohexyl, cyclopentyl and cyclobutyl.

In the context of formula (II) and the group R1, examples of optionally substituted hydrocarbyl groups are the optionally substituted methyl, ethyl and propyl groups in which one of the carbon atoms of the hydrocarbyl group is optionally substituted with O, NH, SO or SO2 . Particular examples of such groups include methyl, ethyl, trifluoromethyl, methyl and ethyl substituted with a carbocyclic or heterocyclic group having from 3 to 12 ring members, sulfonylmethyl substituted with a carbocyclic or heterocyclic group having from 3 to 12 ring members, hydroxymethyl, hydroxyethyl , 3-hydroxy-2-propyl, propyl, isopropyl, butyl and tertiary butyl. Examples of hydrocarbyl groups and carbocyclic and heteroacyl groups are as indicated above in the general definitions of such groups. Particular carbocyclic and heterocyclic groups include unsubstituted or substituted phenyl, indolyl, tetrazolyl, triazolyl, piperidinyl, morpholinyl, piperazinyl, N-methylpiperazinyl, imidazolyl, wherein the optional substituents may be selected from the group R10, and subgroups thereof, as defined herein .

In another subgroup of compounds of formula (II), R1 is a C1-4 hydrocarbyl group optionally substituted with one or more substituents selected from fluoro, hydroxy, C1-4 hydrocarbyloxy, amino, C1-4 mono- or dihydrocarbylamino, and groups carbocyclic or heterocyclic groups having from 3 to 12 ring members, and wherein one of the carbon atoms of the hydrocarbyl group may be optionally substituted with one atom or group selected from O, NH, SO and SO2.

In one embodiment, R1 is a group R1a- (V) n- wherein: n is 0 or 1; V is selected from CH 2, CH 2 CH 2 and SO 2 CH 2; and

Rla is a carbocyclic or heterocyclic group selected from phenyl; five-membered heteroaryl rings having up to 4 heteroatom ring members selected from N, O and S; six-membered heteroaryl rings containing one or two ring nitrogen endocyclic members; five- or six-membered saturated non-aromatic heterocyclic rings containing one or two heteroatom ring members selected from N, O, S and SO2; C 3-6 cycloalkyl groups; indole; and quinoline; wherein each of the carbocyclic and heterocyclic Rla groups may be optionally substituted with one or more substituents selected from five- or six-membered saturated non-aromatic carbocyclic and heterocyclic groups containing up to two heteroatom endocyclic heteroatoms selected from N, O, S and SO 2; hydroxy; amino; oxo; mono-C1-4-alkylamino; di-C 1-4 alkylamino; fluorine; chloro; nitro; C1-4 alkyl (0) wherein q is 0 or 1 and the C1-4 alkyl moiety is optionally substituted with fluoro, hydroxy, C1-2 alkoxy or a five- or six-membered saturated non-aromatic carbocyclic or heterocyclic group containing up to two heteroatom endocyclic members selected from N, O, S and SO2; phenyl and C 1-2 alkylenedioxy.

Specific examples of R1-CO- groups in formula (II) are shown in Table 1 above.

A preferred subgroup of R1-CO groups consists of the groups J, AB, AH, AJ, AL, AS, AX, AY, AZ, BA, BB, BD, BH, BL, BQ and BS.

Another subgroup of R1-CO groups consists of groups A through BF.

Another subgroup of R1-CO groups consists of groups A to BS.

Particularly preferred groups are the groups AJ, BQ and BS in Table 1, e.g. the subset consisting of AJ and BQ.

Another subgroup of compounds of formula (II) may be represented by formula (IV):

or salts or tautomers or N-oxides or solvates thereof; wherein R1 and R2 are as defined herein; an optional second bond may be present between the carbon atoms numbered 1 and 2; one of U and T is selected from CH2, CHR13, CR41R13, NR14, N (O) R15,0 and S (O) t; and the other of U and T is selected from, NR 14, O, CH 2, CHR 11, C (R 41) 2 and C = O; r is 0, 1, 2, 3 or 4; t is 0, 1 or 2; R11 is selected from hydrogen, halogen (particularly fluoro), C1-3 alkyl (e.g., methyl) and C1-3 alkoxy (e.g., methoxy); R 13 is selected from hydrogen, NHR 14, NOH, NOR 14 and Ra-R b; R14 is selected from hydrogen and Rd-Rb;

Rd is selected from a bond, CO, C (X2) X4, SO2 and SChNR0;

Ra, Rb and Rc are as defined above; and R 15 is selected from saturated C 1-4 hydrocarbyl optionally substituted with hydroxy, C 1-2 alkoxy, halogen or a 5- or 6-membered monocyclic carbocyclic or heterocyclic group, with the proviso that U and T can not be simultaneously.

Examples and preferences for the groups R 1 and R 2 are as indicated above for the compounds of formula (II), unless otherwise stated in the context.

In formula (IV), r may be 0, 1, 2, 3 or 4. In one embodiment, r is 0. In another embodiment, r is 2, and in another embodiment r is 4.

In formula (IV), a subset of preferred compounds is the group of compounds in which there is only one single bond between the carbon atoms numbered 1 and 2.

However, in another subset of compounds, there is a double bond between the carbon atoms numbered 1 and 2.

Another subset of compounds is characterized by geminyl disubstitution at carbon 2 (when there is a single bond between carbon numbers 1 and 2) and / or carbon 6. Preferred geminely disubstituents include difluoro and dimethyl.

Another subset of compounds is characterized by the presence of an alkoxy group, for example, a methoxy group on the carbon atom numbered 3, i.e. e., at an α-position relative to the T group.

In formula (IV) are compounds wherein, for example, R 3 is selected from any of the following ring systems:

Preferred ring systems include G1 and G3.

A preferred subgroup of compounds in formula (IV) may be represented by formula (IVa):

or salts or tautomers or N-oxides or solvates thereof; wherein R1 and R2 are as defined above; one of U and T is selected from CH2, CHR13, CR41R13, NR14, N (O) R15,0 and S (O) t; and the other of U and T is selected from CH2, CHR11, C (R11) 2 and C = O; r is 0, 1 or 2; t is 0, 1 or 2; R 11 is selected from hydrogen and C 1-3 alkyl; R13 is selected from hydrogen and Ra-Rb; R14 is selected from hydrogen and Rd-Rb;

Rd is selected from a bond, CO, C (X2) X4, SO2 and SC> 2NRC;

Ra, Rb and Rc are as defined above; and R 15 is selected from saturated C 1-4 hydrocarbyl optionally substituted with hydroxy, C 1-2 alkoxy, halogen or a 5- or 6-membered monocyclic carbocyclic or heterocyclic group.

Examples and preferences for the groups R 1 and R 2 are as indicated above for the compounds of formula (II), unless otherwise stated in the context.

In formula (IVa), T is preferably selected from CH2, CHR13, CR41R13, NR14, N (O) R15,0 and S (O) t; and U is preferably selected from CH 2, CHR 11, C (R 11) 2 and C = O.

In the definitions for the substituents R 11 and R 14, R b is preferably selected from hydrogen; monocyclic carbocyclic and heterocyclic groups having from 3 to 7 ring members; and C1-4 hydrocarbyl (more preferably saturated acyclic C1-4 groups) optionally substituted with one or more substituents selected from hydroxy, oxo, halogen, amino, C1-4 mono- or dihydrocarbylamino, and carbocyclic and heterocyclic groups (more preferably 3 to 6 endocyclic members) and wherein one or more carbon atoms of the C1-4 hydrocarbyl group may be optionally substituted with O, S, SO, SO2, NRC , X 4 C (X 2), C (X 2) X 1; Rc is selected from hydrogen and C1-4 hydrocarbyl; and X 1 is O, S or NRC and X 2 is = O, = S or = NRC. R11 is preferably selected from hydrogen and methyl and most preferably is hydrogen. R 13 is preferably selected from hydrogen; hydroxy; halogen; cyano; amino; saturated C1-4 monohydrocarbylamino; saturated C1-4 dihydrocarbylamino; 5 and 6-membered monocyclic carbocyclic and heterocyclic groups; saturated C 1-4 hydrocarbyl optionally substituted with hydroxy,

C1-2 alkoxy, halogen or a 5- or 6-membered monocyclic carbocyclic or heterocyclic group.

Particular examples of R13 are hydrogen, hydroxyl, amino, C1-2 alkylamino (eg, methylamino) C1-4 alkyl (eg, methyl, ethyl, propyl and butyl), C1-2 alkoxy (eg, methoxy) (Eg, methoxymethyl and methoxyethyl), carboxyl, C1-4 alkoxycarbonyl (eg, C1-4 alkoxycarbonyl, C1-4 alkoxycarbonyl, C1- ethoxycarbonyl) and amino-C 1-2 alkyl (eg, aminomethyl).

Particular examples of R 14 are hydrogen; C1-4 alkyl optionally substituted with fluoro or a saturated five or six membered heterocyclic group (eg, a group selected from (i) methyl, ethyl, n-propyl, i-propyl, butyl, 2,2,2-trifluoroethyl and tetrahydrofuranylmethyl and / or (ii) 2-fluoroethyl and 2,2-difluoroethyl); cyclopropylmethyl; pyridyl-substituted or unsubstituted C1-2 alkyl (e.g., 2-pyridylmethyl); phenyl-substituted or unsubstituted C1-2 alkyl (e.g., benzyl); C1-4 alkoxycarbonyl (e.g., ethoxycarbonyl and t-butyloxycarbonyl); substituted and unsubstituted phenyl-C1-C2-alkoxycarbonyl (e.g., benzyloxycarbonyl); substituted and unsubstituted 5 and 6-membered heteroaryl groups, such as pyridyl (e.g., 2-pyridyl and 6-chloro-2-pyridyl) and pyrimidinyl (e.g., 2-pyrimidinyl); C1- 2-alkoxy-C 1-2 alkyl (e.g., methoxymethyl and methoxyethyl); C1-4 alkylsulfonyl (e.g., methanesulfonyl).

Preferred compounds include those in which (i) U is CHR13 (more preferably CH2) and T is NR14, and (ii) T is CHR13 (more preferably CH2) and U is NR14.

A preferred particular subgroup of compounds of formula (IV) may be represented by formula (Va):

or salts or tautomers or N-oxides or solvates thereof; wherein R14a is selected from hydrogen, C1-4 alkyl optionally substituted with fluoro (eg, methyl, ethyl, n-propyl, i-propyl, butyl and 2,2,2-trifluoroethyl), cyclopropylmethyl, phenyl C 1-2 alkyl (eg, benzyl), C1-4 alkoxycarbonyl (eg, ethoxycarbonyl and t-butyloxycarbonyl), phenyl-C1-C2-alkoxycarbonyl (eg benzyloxycarbonyl), C1- 2-alkoxy-C 1-2 alkyl (eg, methoxymethyl and methoxyethyl) and C1-4 alkylsulfonyl (eg, methanesulfonyl), wherein the phenyl moieties, when present, are optionally substituted with one to three substituents selected from fluoro, chloro, C1-4 alkoxy optionally substituted with fluoro or alkoxy -Ci-2, and C1-4 alkyl optionally substituted with fluoro or C1-2 -alkoxy; w is 0, 1, 2 or 3; R2 is hydrogen or methyl, most preferably hydrogen; R11 and r are as defined above; and R 19 is selected from fluorine; chloro; C 1-4 alkoxy optionally substituted with fluoro or C 1-12 alkoxy; and C 1-4 alkyl optionally substituted with fluoro or C 1-2 alkoxy.

Another preferred particular subgroup of compounds of formula (IV) may be represented by formula (Vb):

or salts or tautomers or N-oxides or solvates thereof; wherein R14a is selected from hydrogen, C1-4 alkyl optionally substituted with fluoro (eg, methyl, ethyl, n-propyl, i-propyl, butyl and 2,2,2-trifluoroethyl), cyclopropylmethyl, phenyl C 1-2 alkyl (eg, benzyl), C1-4 alkoxycarbonyl (eg, ethoxycarbonyl and t-butyloxycarbonyl), phenyl-C1-2 alkoxycarbonyl (eg, benzyloxycarbonyl), C1- 2-alkoxy-C 1-2 alkyl (eg , methoxymethyl and methoxyethyl) and C1-4 alkylsulfonyl (eg methanesulfonyl), wherein the phenyl moieties, when present, are optionally substituted with one to three substituents selected from fluoro, chloro, C1-4 alkoxy optionally substituted by fluoro or alkoxy -Ci-2, and C1-4 alkyl optionally substituted with fluoro or C1-2 -alkoxy; w is 0, 1, 2 or 3; R2 is hydrogen or methyl, most preferably hydrogen; R11 and r are as defined above; and R 19 is selected from fluorine; chloro; C 1-4 alkoxy optionally substituted with fluoro or C 1-12 alkoxy; and C 1-4 alkyl optionally substituted with fluoro or C 1-2 alkoxy.

In formula (Va) and (Vb), when w is 1, 2 or 3, it is preferred that the phenyl ring is 2-monosubstituted, 3-monosubstituted, 2,6-disubstituted, 2,3-disubstituted, 2,4- 2,5-disubstituted, 2,3,6-trisubstituted or 2,4,6-trisubstituted. Most preferably the phenyl ring is disubstituted at the 2- and 6-positions with substituents selected from fluoro, chloro and methoxy. R11 is preferably hydrogen (or r is 0). R14a is most preferably hydrogen or methyl.

A preferred subgroup of compounds of formula (Va) may be represented by the formula (Way):

or salts or tautomers or N-oxides or solvates thereof; wherein R 20 is selected from hydrogen and methyl; R 21 is selected from fluorine and chlorine; and R22 is selected from fluoro, chloro and methoxy; or one of R 21 and R 22 is hydrogen and the other is selected from chloro, methoxy, ethoxy, difluoromethoxy, trifluoromethoxy and benzyloxy.

Another preferred subgroup of compounds of formula (Va) may be represented by formula (VIb):

or salts or tautomers or N-oxides or solvates thereof; wherein R 20 is selected from hydrogen and methyl; R 21a is selected from fluorine and chlorine; and R 22a is selected from fluoro, chloro and methoxy.

Particular compounds in formula (VIb) include: 4- (2,6-Difluoro-benzoylamino) -pyrazole-3-carboxylic acid piperidin-4-ylamide; 4- (2,6-Difluoro-benzoylamino) -1H-pyrazole-3-carboxylic acid (1-methyl-piperidin-4-yl) -amide; 4- (2,6-Dichloro-benzoylamino) -1H-pyrazole-3-carboxylic acid piperidine-4-carboxylic acid; and 4- (2-fluoro-6-methoxybenzoylamino) -1H-pyrazole-3-carboxylic acid piperidin-4-ylamide; or salts or tautomers or N-oxides or solvates thereof. (II) For the avoidance of doubt, it is to be understood that each preference, embodiment and general and specific example of the R 1 groups may be combined with each preference, embodiment and general and specific example of the R 2 and / or R 3 groups and / or R4 and / or R10 and / or Y and / or Rg and / or its subgroups as defined herein and that all such combinations are covered by this application.

The various functional groups and substituents which constitute the compounds of formula (II) are typically chosen such that the molecular weight of the compound of formula (II) does not exceed 1000. More generally, the molecular weight of the compound will be less than 750, per less than 700, or less than 650, or less than 600, or less than 550. More preferably, the molecular weight is less than 525 and, for example, is 500 or less.

Particular compounds of formula (II) are as illustrated in the examples below.

Salts, Solvates, Tautomers, Isomers, N-Oxides, Esters,

Prodrugs and Isotopes

Unless otherwise noted, a reference to a particular compound also includes the ionic, salt, solvate protected forms thereof, for example, as discussed below.

Many compounds of formula (II) may exist in the form of salts, for example acid addition salts or, in some cases, salts of organic and inorganic bases, such as carboxylate, sulfonate and phosphate salts. All such salts are within the scope of this invention and references to compounds of formula (II) include the salt forms of the compounds. As in the previous sections of this application, all references to formula (II) are to be taken to refer also to formulas (IV), (IVa), (Va), (Vb), (Way) or (VIb) and to their subgroups, unless the context indicates otherwise.

The salt forms may be selected and prepared according to methods described in Pharmaceutical Salts: Properties, Selection, and Use, P. Heinrich Stahl (Editor), Camille G. Wermuth (Editor), ISBN: 3-90639-026-8 , hardcover book, 388 pages, August 2002.

The acid addition salts may be prepared with a wide variety of inorganic and organic acids. Examples of acid addition salts include salts prepared with an acid selected from the group consisting of acetic, 2,2-dichloroacetic, adipic, alginic, ascorbic (eg, L-ascorbic), L-aspartic, benzenesulfonic, benzoic, 4- acetamidobenzoic, butanoic, (+) camphoric, camphorsulfonic, (+) - (1S) -camphor-10-sulfonic, capric, caprylic, caprylic, cinnamic, citric, cyclamic, dodecylsulfuric, ethane-1,2-disulfonic, ethanesulfonic, glucuronic (eg, D-glucuronic), glutamic (eg, L-glutamic), α-oxoglutaric, glycolic, hippuric, hydrobromic, hydrochloric, hydroiodic hydrochloric, hydrobromic, hydrobromic, hydroxysulphonic, (±) -L-lactic, (±) -DL-lactic, lactobionic, maleic, malic, (-) -L-malic, malonic, (±) -DL-mandelic, methanesulfonic, naphthalene-2-sulfonic , naphthalene-1,5-disulfonic, 1-hydroxy-2-naphthoic, nicotinic, nitric, oleic, orotic, ox (+) - L-tartaric, thiocyanic, p-toluenesulfonic, undecylenic and valeric acids, which are unsaturated, unsaturated, as well as acylated amino acids and cation exchange resins.

A particular group of salts consists of salts prepared from hydrochloric, hydroiodic, phosphoric, nitric, sulfuric, citric, lactic, succinic, maleic, malic, isethionic, fumaric, benzenesulfonic, toluenesulfonic, methanesulfonic, ethanesulfonic, naphthalenesulfonic, valeric, acetic , propanoic, butanoic, malonic, glucuronic and lactobionic acids.

A preferred group of salts consists of salts prepared from hydrochloric, acetic, adipic, L-aspartic and DL-lactic acids.

Particularly preferred salts are hydrochloride salts.

For example, if the compound is anionic, or has a functional group which may be anionic (e.g., -COOH may be -COO-), then a salt with a suitable cation may be prepared. Examples of suitable inorganic cations include, but are not limited to, alkali metal ions such as Na + and K +, alkaline earth cations such as Ca 2+ and Mg 2+, and other cations such as Al 3+. Examples of suitable organic cations include, but are not limited to, ammonium ion (i.e., NH4 +) and substituted ammonium ions (e.g., NH3R +, NH2R2 +, NHR3 +, NR4 +). Examples of some suitable substituted ammonium ions are those derived from: ethylamine, diethylamine, dicyclohexylamine, triethylamine, butylamine, ethylenediamine, ethanolamine, diethanolamine, piperazine, benzylamine, phenylbenzylamine, choline, meglumine and tromethamine, as well as amino acids such as lysine and arginine. An example of a common quaternary ammonium ion is N (CH 3) 4+.

When the compounds of the formula (II) contain an amine function, they may form quaternary ammonium salts, for example by reaction with an alkylating agent according to methods well known to the person skilled in the art. Such quaternary ammonium compounds are within the scope of formula (II).

The salt forms of the compounds of the formula (II) are typically pharmaceutically acceptable salts, and examples of pharmaceutically acceptable salts are discussed in Berge et al. , 1977, " Pharmaceutically Acceptable Salts ", J. Pharm. Sci., Vol. 66, pp. 1-19. However, salts which are not pharmaceutically acceptable may also be prepared as intermediate forms which may then be converted into pharmaceutically acceptable salts. Such non-pharmaceutically acceptable salt forms, which may be useful, for example, in the purification or separation of the compounds of formula (II), are also part of the invention.

Compounds of formula (II) containing an amine function may also form N-oxides. Reference herein to a compound of formula (II) which contains an amine function also includes N-oxide.

When a compound contains several amine functions, one or more than one nitrogen atom may be oxidized to form an N-oxide. Particular examples of N-oxides are the N-oxides of a tertiary amine or a nitrogen atom of a nitrogen-containing heterocycle.

The N-oxides may be prepared by treatment of the corresponding amine with an oxidizing agent, such as hydrogen peroxide or a peracid (eg, peroxycarboxylic acid), see for example, Advanced Organic Chemistry, Jerry March, 4th Edition, Wiley Interscience, pages. More particularly, the N-oxides can be prepared by the method of LW Deady (Syn. Comm. 1977, 7, 509-514) in which the amine compound is reacted with m-chloroperoxybenzoic acid (MCPBA), for example, inert solvent such as dichloromethane.

The compounds of formula (II) may exist in a number of different geometric and tautomeric isomeric forms and references to compounds of formula (II) include all such forms. For the avoidance of doubt, when a compound can exist in one of several geometric or tautomeric isomeric forms and is only specifically described or shown one, all the others are nevertheless encompassed by formula (II).

For example, in the compounds of formula (II), the pyrazole group may acquire any of the following two tautomeric forms A and B (wherein X represents R 1 (CO) NH). To facilitate, general formula (II) illustrates Form A but the formula is to be considered as encompassing both tautomeric forms.

Further examples of tautomeric forms include, for example, the keto, enol and enolate forms, for example, in the following tautomeric moieties: keto / enol (shown below), imine / enamine, amide / iminoalcohol, amidine / amidine, oxime, thioketone / enetiol, and nitro / acyl-nitro.

When the compounds of formula (II) contain one or more chiral centers, and may exist as two or more optical isomers, references to compounds of formula (II) include all isomeric optical forms thereof (eg, enantiomers, epimers, and diastereomers), as individual optical isomers, or mixtures (eg, racemic mixtures) or two or more optical isomers, unless the context otherwise requires.

Optical isomers can be characterized and identified by their optical activity (i.e. as + and - isomers or del isomers) or can be characterized in terms of their absolute stereochemistry using the nomenclature " R and S " developed by Cahn, Ingold and Prelog, see Advanced Organic Chemistry of Jerry March, 4th Edition, John Wiley & Sons, Nova

York, 1992, pages 109-114, and see also Cahn, Ingold & Prelog, Angew. Chem. Int. Ed. Engl., 1966, 5, 385-415.

Optical isomers can be separated by a number of techniques including chiral chromatography (chromatography on a chiral support) and such techniques are well known to the person skilled in the art.

When the compounds of formula (II) exist as two or more optical isomeric forms, one enantiomer in one pair of enantiomers may exhibit advantages over the other enantiomer, for example in terms of biological activity.

Thus, in certain circumstances, it may be desirable to use as a therapeutic agent only one of a pair of enantiomers, or only one of a multiplicity of diastereoisomers. Accordingly, the invention provides compositions containing a compound of formula (II) having one or more chiral centers, wherein at least 55% (eg, at least 60%, 65%, 70%, 75%, 80%, 85% , 90% or 95%) of the compound of formula (II) is present as a single optical isomer (eg, enantiomer or diastereoisomer). In a general embodiment, 99% or more (e.g., substantially all) of the total amount of the compound of formula (II) may be present as a single optical isomer (e.g., enantiomer or diastereoisomer).

The compounds of the formula (II) include compounds with one or more isotopic substitutions and a reference to a particular element includes within it all the isotopes of the element. For example, a reference to hydrogen includes within its scope 2H, 2H (D), and 3H (T). Similarly, references to carbon and oxygen include within their scope 12C, 13C and 14C and 160 and 18, respectively.

The isotopes may be radioactive or non-radioactive. In one embodiment of the invention, the compounds do not have any radioactive isotopes. Such compounds are preferred for therapeutic use. In another embodiment, however, the compound may contain one or more radioisotopes. Compounds containing such radioisotopes may be useful in a diagnostic setting.

Esters such as the carboxylic acid esters and acyloxyl esters of the compounds of formula (II) having a carboxylic acid group or a hydroxyl group are also encompassed by Formula (II). Examples of esters are compounds containing the group -C (= O) OR, where R is an ester substituent, for example, a C1-7 alkyl group, a C3-20 heterocyclyl group or a C5-20 aryl group, of a preferred mode is a C 1-7 alkyl group. Particular examples of ester groups include, but are not limited to, -C (= O) OCH 3, C (= O) OCH 2 CH 3, -C (= O) O C (CH 3) 3 and -C (= O) O Ph. Examples of acyloxy groups (inverse ester) are represented by -O C (= O) R, where R is an acyloxy substituent, for example a C1-7 alkyl group, a C3-20 heterocyclyl group or a C5- 20, preferably a C 1-7 alkyl group. Particular examples of acyloxy groups include, but are not limited to, -O (O) O (acetoxy), -OC (= O) CH 2 CH 3, -O C (= O) C (CH 3) 3, -OC ) Ph and -OC (= O) CH2 Ph.

Also encompassed by formula (II) are any polymorphic forms of the compounds, solvates (e.g., hydrates) and complexes (e.g., inclusion complexes or clathrates with compounds, such as cyclodextrins, or complexes with metals) of the compounds. For example, some prodrugs are esters of the active compound (e.g., a physiologically acceptable metabolically unstable ester). During metabolism, the ester group (-C (= O) OR) is cleaved to produce the active drug. Such esters may be prepared by esterifying, for example, any of the carboxylic acid groups (-C (= O) OH) in the parent compound with, where appropriate, prior protection of any other reactive groups present in the parent compound, followed by deprotection if required.

Examples of such metabolically unstable esters include those of the formula wherein R is: C 1-7 -alkyl (eg, -Me, -Et, -nPr, -iPr, -nBu, -sBu, -iBu , -tBu); C 1-7 aminoalkyl (e.g., aminoethyl; 2- (N, N-diethylamino) ethyl; 2- (4-morpholino) ethyl); and acyloxy-C1-7 alkyl (eg, acyloxymethyl, acyloxyethyl, pivaloyloxymethyl, acetoxymethyl, 1-acetoxyethyl, 1- (1-methoxy-1-methyl) ethylcarbonyloxyethyl, 1- (benzoyloxy) ethyl, isopropoxycarbonyloxymethyl, 1- (4-tetrahydropyranyloxy) carbonyloxymethyl, 1- (4-tetrahydropyranyloxymethyl) cyclohexylcarbonyloxymethyl, 1-cyclohexylcarbonyloxymethyl, 1-cyclohexylcarbonyloxyethyl, tetrahydropyranyl) carbonyloxyethyl; (4-tetrahydropyranyl) carbonyloxymethyl; and 1- (4-tetrahydropyranyl) carbonyloxyethyl).

Also, some prodrugs are enzymatically activated to produce the active compound, or a compound which, upon subsequent chemical reaction, produces the active compound (for example, as in ADEPT, GDEPT, LIDEPT, etc.). For example, the prodrug may be a sugar derivative or other conjugated glycoside, or may be an amino acid ester derivative.

Biological Activity

The compounds of the formulas (II), (IV), (IVa), (Va), (Vb), (Via) or (VIb) and their subgroups are inhibitors of cyclin-dependent kinases, and in particular selected cyclin-dependent kinases of CDK1, CDK2, CDK3, CDK4, CDK5 and CDK6.

Preferred compounds are compounds which inhibit one or more CDK kinases selected from CDK1, CDK2, CDK4 and CDK5, for example, CDK1 and / or CDK2.

The compounds of formula (II) are also considered to be glycogen synthase kinase-3 (GSK3) inhibitors.

As a consequence of their activity in modulating or inhibiting CDK kinases and glycogen synthase kinase they are expected to be useful in providing a means of stopping or regaining control of the cell cycle in abnormal dividing cells. Accordingly, it is anticipated that the compounds will be useful in the treatment or prevention of proliferative disorders, such as cancers. It is also envisaged that the compounds of formula (II) will be useful in the treatment of conditions such as, for example, viral infections, type II or non-insulin dependent diabetes mellitus, autoimmune diseases, head trauma, stroke, epilepsy, neurodegenerative diseases such as Alzheimer's, motor neuron disease, progressive supranuclear palsy, corticobasal degeneration and Pick's disease. A subgroup of conditions and pathological conditions in which the compounds of formula (II) are expected to be useful consists of viral infections, autoimmune diseases and neurodegenerative diseases.

CDKs play a role in cell cycle regulation, apoptosis, transcription, differentiation and CNS function. Accordingly, CDK inhibitors could be useful in the treatment of diseases in which there is a disorder of proliferation, apoptosis or differentiation such as cancer. In particular, RB + tumors may be particularly sensitive to CDK inhibitors. RB-vo tumors may also be sensitive to CDK inhibitors.

Examples of cancers that may be inhibited include, but are not limited to, a carcinoma, e.g. a bladder, breast, colon carcinoma (eg, colorectal carcinomas such as colon adenocarcinoma and colon adenoma), kidney, epidermis , liver, lung, e.g., adenocarcinoma, small cell lung cancer, and non-small cell lung carcinomas, esophagus, gallbladder, ovary, pancreas, e.g. exocrine pancreatic carcinoma, stomach, cervix, thyroid, prostate or skin, for example, squamous cell carcinoma; a hematopoietic lymphoid lineage tumor, for example, leukemia, acute lymphocytic leukemia, B-cell lymphoma, T-cell lymphoma, Hodgkin's lymphoma, non-Hodgkin's lymphoma, trichocellin lymphoma or Burkett's lymphoma; a hematopoietic tumor of myeloid lineage, for example, acute and chronic myeloid leukemias, myelodysplastic syndrome or promyelocytic leukemia; thyroid follicular cancer; a tumor of mesenchymal origin, for example, fibrosarcoma or rhabdomyosarcoma, a tumor of the central or peripheral nervous system, for example, astrocytoma, neuroblastoma, glioma or schwannoma; melanoma; seminoma; teratocarcinoma; osteosarcoma; xeroderma pigmentosum; keratoacanthoma; thyroid follicular cancer; or Kaposi's sarcoma.

Cancers can be cancers that are sensitive to inhibition of any of the cyclin dependent kinases selected from CDK1, CDK2, CDK3, CDK4, CDK5 and CDK6, for example, one or more CDK kinases selected from CDK1, CDK2, CDK4 and CDK5, and. CDK1 and / or CDK2.

Whether or not a particular cancer is one that is sensitive to inhibition by a cyclin-dependent kinase can be determined by means of a cell growth assay as indicated in Example 250 below or by a method as indicated in the section entitled " Methods of Diagnosis ".

CDKs are also known to play a role in apoptosis, proliferation, differentiation and transcription, and therefore CDK inhibitors could also be useful in the treatment of the following diseases other than cancer; viral infections, e.g. herpes viruses, variola virus, Epstein-Barr virus, Sindbis virus, adenovirus, HIV, HPV, HCV and HCMV; prevention of AIDS development in HIV-infected individuals; chronic inflammatory diseases, for example, disseminated lupus erythematosus, autoimmune mediated glomerulonephritis, rheumatoid arthritis, psoriasis, inflammatory bowel disease and autoimmune diabetes mellitus; cardiovascular diseases, for example, cardiac hypertrophy, restenosis, atherosclerosis; neurodegenerative disorders, for example, Alzheimer's disease, AIDS-related dementia, Parkinson's disease, amyotrophic lateral sclerosis, retinitis pigmentosa, spinal muscular atrophy and cerebellar degeneration; glomerulonephritis; myelodysplastic syndromes, ischemic injury associated with myocardial infarction, stroke and reperfusion injury, arrhythmia, atherosclerosis, toxin-induced or alcohol-related liver diseases, hematological diseases, eg, chronic anemia and aplastic anemia; degenerative diseases of the musculoskeletal system, for example, osteoporosis and arthritis, aspirin-sensitive rhinosinusitis, cystic fibrosis, multiple sclerosis, renal diseases and cancer pain.

It has also been found that certain cyclin-dependent kinase inhibitors may be used in combination with other anticancer agents. For example, the cyclin-dependent kinase inhibitor flavopiridol has been used with other anticancer agents in combination therapy.

Thus, in the pharmaceutical compositions, uses or methods of this invention for the treatment of a disease or condition comprising abnormal cell growth, the disease or condition comprising abnormal cell growth carrying out is in the form of a cancer.

A group of cancers include human breast cancers (e.g., primary breast tumors, breast cancer with lymph node-negative, invasive ductal adenocarcinomas of the breast, non-endometrioid breast cancers); and mantle cell lymphomas. In addition, other cancers are colorectal and endometrial cancers.

Another subset of cancers include breast cancer, ovarian cancer, colon cancer, prostate cancer, esophageal cancer, squamous cancer and non-small cell lung carcinomas. The activity of the compounds of formula (II) as inhibitors of cyclin-dependent kinases and of glycogen synthase kinase-3 can be measured using the assays set forth in the examples below and the level of activity displayed for a given compound can be defined in terms of value of IC50. Preferred compounds of the present invention are compounds having an IC 50 value of less than 1 micromole, more preferably less than 0.1 micromole. Methods for the Preparation of Compounds of Formula (II)

The compounds of formula (II) and the various subgroups thereof may be prepared according to methods of synthesis well known to the person skilled in the art. Unless otherwise indicated, R 1, R 2, R 3 and Y are as defined above.

In this section, as in all other sections of this application, references to formula (II) are to be taken to refer also to formulas (IV), (IVa), (Va), (Vb), (Way) or (VIb) and subgroups thereof, unless the context otherwise indicates.

The compounds of formula (II) may be prepared by reacting a carboxylic acid of the formula R 1 -CO 2 H or an activated derivative thereof with an appropriately substituted 4-amino-pyrazole as shown in Scheme 1.

The starting material for the synthetic route shown in Scheme 1 is 4-nitro-pyrazole-3-carboxylic acid (X) which can be obtained commercially or can be prepared by nitration of the corresponding unsubstituted carboxyl pyrazole compound at the 4. The 4-nitro-pyrazole carboxylic acid (X), or a reactive derivative thereof, is reacted with the amine H2 N-Y-R3 to give the 4-nitro-amide (XI). The coupling reaction between the carboxylic acid (X) and the amine is preferably carried out in the presence of a reagent of the type generally used in the formation of peptide bonds. Examples of such reagents include 1,3-dicyclohexylcarbodiimide (DCC) (Sheehan et al., J. Amer.Chem.Soc. 1955, 77, 1067), 1-ethyl-3- (3'-dimethylaminopropyl) carbodiimide referred to as EDC or EDAC but also known in the art as EDCI and WSCDI) (Sheehan et al, J. Org. Chem., 1961, 26, 2525), uronium-based coupling agents such as O-.beta.-hexafluorophosphate (HATU) and phosphonium-based coupling agents such as 1-benzo-triazolyloxytris (pyrrolidino) phosphonium hexafluorophosphate (PyBOP) (Castro et al. al., Tetrahedron Letters, 1990, 31, 205). Carbodiimide-based coupling agents are advantageously used in association with 1-hydroxy-7-azabenzotriazole (HOAt) (LA Carpino, J. Amer. Chem. Soc., 1993, 115, 4397) or 1-hydroxybenzotriazole (HOBt) (Konig et al., Chem. Ber., 103, 708, 2024-2034). Preferred coupling reagents include EDC (EDAC) and DCC in association with HOAt or HOBt. The coupling reaction is typically performed in a non-protic, non-aqueous solvent such as acetonitrile, dioxane, dimethylsulfoxide, dichloromethane, dimethylformamide or N-methylpyrrolidine, or in an aqueous solvent optionally together with one or more miscible cosolvents. The reaction may be carried out at room temperature or, where the reactants are less reactive (for example in the case of electron-deficient anilines having electron withdrawing groups, such as the sulfonamide groups) at a suitably high temperature. The reaction may be carried out in the presence of a non-interfering base, for example a tertiary amine such as triethylamine or N, N-diisopropylethylamine.

As an alternative, a reactive derivative of the carboxylic acid can be used, e.g. an acid anhydride or chloride. Reaction with a reactive derivative such as an anhydride is typically achieved by stirring the amine and the anhydride at room temperature in the presence of a base such as pyridine.

The amines of formula H2N-Y-R3 may be obtained from commercial sources or may be prepared by any of a large number of standard synthetic methods well known to those skilled in the art, see for example, Advanced Organic Chemistry of Jerry March, 4th Edition, John Wiley & Sons, 1992, and Organic Synthesis, Volumes 1-8, John Wiley, edited by Jeremiah P. Freeman (ISBN: 0-471-31192-8), 1995, and see also the methods described in the experimental section below. The nitro-pyrazole amide (XI) is reduced to give the corresponding 4-amino compound of formula (XII). The reduction may be carried out by standard methods such as catalytic hydrogenation, for example in the presence of palladium on charcoal in a polar solvent such as ethanol or dimethylformamide at room temperature. As an alternative, the reduction may be effected using a reducing agent such as tin (II) chloride in ethanol, typically with heating, for example at the reflux temperature of the solvent. The 4-amino-pyrazole compound (XII) is then reacted with a carboxylic acid of the formula (IV-CChH) or a reactive derivative thereof using the methods and conditions described above for amide formation (XI) to give compound of formula (II).

The carboxylic acids of the formula R 1 -CO 2 H may be obtained commercially or may be synthesized according to methods well known to the person skilled in the art, see, for example, Advanced Organic Chemistry and Organic Synthesis, details of which are given above.

In an alternative synthetic route, the compounds of formula (II) may be prepared by reacting a compound of formula (XIII) (wherein X represents R 1 (CO) NH) with a compound of the formula R 3 -Y-NH 2. The reaction can be carried out using the amide coupling conditions described above.

Once formed, a compound of formula (II) may be transformed into another compound of formula (II) using standard chemical procedures well known in the art. For examples of functional group interconversions see, for example, Fiesers' Reagents for Organic Synthesis, Volumes 1-17, John Wiley, edited by Mary Fieser (ISBN: 0-471-58283-2) and Organic Synthesis, Volumes 1-8 , John Wiley, edited by Jeremiah P. Freeman (ISBN: 0-471-31192-8), 1995.

The starting materials for the synthetic routes shown in the Schemes above, e.g. pyrazoles of formula (X), may be obtained commercially or may be prepared by methods known to those skilled in the art. These can be obtained using known methods, e.g. of ketones, such as in a process described in EP308020 (Merck), or the methods discussed by Schmidt in Helv. Chim. Acta., 1956, 39, 986-991 and Helv. Chim. Acta., 1958, 41, 306-309. Alternatively, these may be obtained by conversion of a commercially available pyrazole, for example those containing halogen, nitro, ester or amide functionalities, into pyrazoles containing the desired functionality by standard methods known to a person skilled in the art. For example, in 3-carboxy-4-nitropyrazole, the nitro group can be reduced to an amine by standard methods. The 4-nitro-pyrazole-3-carboxylic acid (XII) can be obtained commercially or can be prepared by nitration of the corresponding unsubstituted carboxyl pyrazole compound at the 4-position, and the halogen-containing pyrazoles can be used in coupling reactions with tin or palladium chemistry.

Protection Groups

In many of the reactions described above it may be necessary to protect one or more groups to prevent reaction occurring at an undesirable location of the molecule. Examples of protecting groups, and methods of protecting and deprotecting functional groups, can be found in Protective Groups in Organic Synthesis (T. Green and P. Wuts, 3rd Edition, John Wiley and Sons, 1999).

For example, a hydroxyl group may be protected as an ether (-OR) or an ester (-OC (= O) R), for example as: a t-butyl ether; a tetrahydropyranyl ether (THP); a benzyl ether, benzhydryl (diphenylmethyl) or trityl (triphenylmethyl); a trimethylsilyl or t-butyldimethylsilyl ether; or an acetyl ester (-OC (= O) CH 3, -OAc).

An aldehyde or ketone group may be protected, for example, as an acetal (R-CH (OH) 2) or ketal (R2C (OR) 2), respectively, in which the carbonyl group (> C = O) is converted in a diether (> C (O R) 2) by reaction with, for example, a primary alcohol. The aldehyde or ketone group is readily regenerated by hydrolysis using a large excess of water in the presence of acid.

An amine group may be protected, for example, as an amide (-NRCO-R) or a urethane (-NRCO-OR), for example, as: a methylamide (-NHCO-CH 3); a benzyloxylamide (-NHCO-OCH2 C6 H5, -NH-Cbz or NH-Z); as a t-butoxylamide (-NHCO-OC (CH 3) 3, -NH-Boc); (-NHCO-OC (CH3) 2 C6 H4 C6 H5, -NH-Bpoc), as a 9-fluorenylmethoxylamide (-NH-Fmoc), as a 6-nitroveratryloxylamide (-NH-Nvoc), as a 2-biphenyl-2-propoxylamide a 2-trimethylsilylethyloxylamide (-NH-Teoc), as a 2,2,2-trichloroethyloxylamide (-NH-Troc), as an allyloxylamide (-NH-Alloc) or as a 2- (-phenylsulfonyl) ethyloxylamide (-NH-Psec ).

For example, in Scheme 1 above, when the R 3 moiety in the amine H 2 N-Y-R 3 contains a second amino group, such as a cyclic amino group (eg, a piperidine or pyrrolidine group), the second amino group can be protected by means of a protecting group as defined above, a preferred group being the tert-butyloxycarbonyl (Boc) group. Where subsequent modification of the second amino group is not required, the protecting group may be brought throughout the reaction sequence to give an N-protected form of a compound of formula (II), which may then be deprotected by standard methods (eg , acid treatment in the case of the Boc group) to give the compound of formula (II).

Other protecting groups for amines, such as cyclic amines and heterocyclic NH groups, include toluenesulfonyl (tosyl) and methanesulfonyl (mesyl) groups, benzyl groups such as para-methoxybenzyl (PMB) groups and tetrahydropyranyl (THP) .

A carboxylic acid group may be protected as an ester, for example, as: a C 1-7 alkyl ester (e.g., a methyl ester, a t-butyl ester); a C 1-7 haloalkyl ester (e.g., a C 1-7 trihaloalkyl ester); a tri-C 1-7 alkylsilyl-C 1-7 alkyl ester; or a C5-20 aryl C1-7 alkyl ester (e.g., a benzyl ester, a nitrobenzyl ester); or as an amide, for example as a methylamide. A thiol group may be protected, for example, as a thioether (-SR), for example as: a benzyl thioether; an acetamidomethyl ether (-S-CH 2 NHC (= O) CH 3).

Isolation and purification of the compounds of formula (II)

The compounds of formula (II) may be isolated and purified according to standard techniques well known to the person skilled in the art. One technique of particular utility in the purification of the compounds is preparative liquid chromatography using mass spectrometry as a means of detecting the purified compounds emerging from the chromatography column. Preparative LC-MS is a standard and efficient method used for the purification of small organic molecules, such as the compounds described herein. Methods for liquid chromatography (LC) and mass spectrometry (MS) may be modified to provide better separation of raw materials and improve MS detection of the samples. The optimization of the preparative gradient LC method will involve the modification of columns, eluents and volatile modifiers, and gradients. Methods for optimizing preparative LC-MS methods and for using them to purify compounds are well known in the art. Such methods are described in Rosentreter U, Huber U .; Optimal fraction collecting in preparative LC / MS; J Comb Chem .; 2004; 6 (2), 159-64 and Leister W, Strauss K, Wisnoski D, Zhao Z, Lindsley C., Development of a custom high throughput preparative liquid chromatography / mass spectrometer for the preparative purification and analytical analysis of compound libraries; J Comb Chem .; 2003; 5 (3); 322-9.

An example of such a system for purifying compounds via preparative LC-MS is described below in the Examples section of this application (under the heading " LC-MS System for Mass Co-ordinated Purification "). However, it will be understood that alternative systems and methods to those described could be used. In particular, standard phase preparative LC based methods may be used instead of the reverse phase methods described herein. Most preparative LC-MS systems utilize reverse phase LC and volatile acid modifiers, since the approach is very effective for purification of small molecules and because the eluents are compatible with positive ion electrospray mass spectrometry. The use of other chromatographic solutions, e.g. normal phase LC, alternatively buffered mobile phase, basic modifiers etc. as outlined in the analytical methods described below could alternatively be used to purify the compounds.

Pharmaceutical formulations

Although the active compound may be administered alone, it is preferred to present it as a pharmaceutical composition (eg, formulation) comprising at least one active compound of the invention together with one or more carriers, adjuvants, excipients, diluents, fillers, buffers , stabilizers, preservatives, pharmaceutically acceptable lubricants, or other materials well known to those skilled in the art and, optionally, other therapeutic or prophylactic agents.

Thus, the present invention further provides pharmaceutical compositions as defined above, and methods of preparing a pharmaceutical composition comprising the combination of at least one active compound, as defined above, together with one or more carriers, excipients, buffers, adjuvants, stabilizers , or other pharmaceutically acceptable materials, as described herein. The term " pharmaceutically acceptable " as used herein refers to compounds, materials, compositions and / or dosage forms which are, within the scope of a sound medical opinion, suitable for use in contact with the tissues of an individual (eg, human) without toxicity, irritation, allergic response, or other problem or excessive complication, provided with a reasonable benefit / risk ratio. Each vehicle, excipient, etc. must also be " acceptable " in the sense of being compatible with the other ingredients of the formulation.

Accordingly, in a further aspect, the invention provides compounds of the formula (II) and its subgroups, such as formulas (IV), (IVa), (Va), (Vb), (Way) or (VIb) and their subgroups as defined herein in the form of pharmaceutical compositions.

The pharmaceutical compositions may be in any form suitable for oral, parenteral, topical, intranasal, ophthalmic, optical, rectal, intravaginal or transdermal administration. When the compositions are intended for parenteral administration, they may be formulated for intravenous, intramuscular, intraperitoneal, subcutaneous or for direct administration to a target organ or tissue by injection, infusion or other means of administration.

In a preferred embodiment of the invention, the pharmaceutical composition is in a form suitable for i.v. administration, for example, by injection or infusion.

In another preferred embodiment, the pharmaceutical composition is in a form suitable for subcutaneous (s.c.) administration.

Suitable pharmaceutical dosage forms for oral administration include tablets, capsules, oval tablets, pills, lozenges, syrups, solutions, powders, granules, elixirs and suspensions, sublingual tablets, wafers or adhesives and mouthpieces.

Pharmaceutical compositions containing compounds of formula (II) may be formulated according to known techniques, see for example, Remington's Pharmaceutical Sciences, Mack

Publishing Company, Easton, PA, USA.

Thus, the tablet compositions may contain a unit dosage of active compound together with an inert diluent or carrier, such as a sugar or sugar alcohol, e.g. g. ; lactose, sucrose, sorbitol or mannitol; and / or a non-sugar diluent, such as sodium carbonate, calcium phosphate, calcium carbonate, or a cellulose or derivative thereof, such as methylcellulose, ethylcellulose, hydroxypropylmethylcellulose, and starches such as corn starch. The tablets may also contain standard ingredients, such as binders and granulating agents, such as polyvinylpyrrolidone, disintegrants (eg, expandable crosslinked polymers, such as crosslinked carboxymethylcellulose), lubricants (eg, stearates), preservatives (eg, parabens), antioxidants ( eg, BHT), buffering agents (for example, phosphate or citrate buffers), and effervescent agents, such as citrate / bicarbonate mixtures. Such excipients are well known and need not be discussed here in detail.

The capsule formulations may be of the hard gelatin variety or soft gelatin and may contain the active component in the solid, semi-solid or liquid form. Gelatin capsules may be prepared from animal gelatin or their equivalents of synthetic or vegetable origin.

Solid dosage forms (eg, tablets, capsules, etc.) may be coated or uncoated, but typically have a coating, for example a film-protecting coating (eg, a wax or lacquer) or a controlled release coating . The coating (e.g., an Eudragit ™ type polymer) may be designed to release the active component at a desired location within the gastrointestinal tract. Thus, the coating may be selected so as to degrade under certain pH conditions in the gastrointestinal tract, thereby selectively releasing the compound in the stomach or the ileum or duodenum.

In place of or in addition to a coating, the drug may be presented in a solid matrix comprising a release-controlling agent, for example a release-delay agent which may be adapted to selectively release the compound under varying acidity or alkalinity conditions in the gastrointestinal tract. Alternatively, the matrix material or release delay coating may take the form of an erodible polymer (e.g., a maleic anhydride polymer) which is substantially continuously eroded as the dosage form passes through the gastrointestinal tract. As a further alternative, the active compound may be formulated into an administration system which provides osmotic control of the release of the compound. Osmotic release and other sustained release or sustained release formulations may be prepared according to methods well known to those skilled in the art.

Compositions for topical use include ointments, creams, spray formulations, adhesives, gels, liquid droplets and implants (for example, intraocular implants). Such compositions may be formulated according to known methods.

Compositions for parenteral administration are typically presented as aqueous or oily solutions or sterile suspensions, or may be provided in the form of finely divided sterile powder for extemporaneous preparation with sterile water for injection.

Examples of formulations for rectal or intravaginal administration include pessaries and suppositories which may be, for example, prepared from a moldable or waxed profile material containing the active compound.

Compositions for administration by inhalation may take the form of inhalable powder compositions or formulations for spraying liquid or powder, and may be administered in a standard manner using powder inhaler devices or aerosol delivery devices. Such devices are well known. For administration by inhalation, the powdered formulations typically comprise the active compound together with a solid inert powder diluent such as lactose.

The compounds of formula (II) will generally be presented in unit dosage form and, as such, will typically contain sufficient compound to provide a desired level of biological activity. For example, a formulation intended for oral administration may contain from 0.1 milligrams to 2 grams of active ingredient, more generally from 10 milligrams to 1 grams, for example, 50 milligrams to 500 milligrams. The active compound will be administered to a patient in need thereof (e.g., a human or a diseased animal) in an amount sufficient to achieve the desired therapeutic effect. Treatment Methods

The compounds of formula (II) and their subgroups, such as formulas (IV), (IVa), (Va) (Vb), (Way) or (VIb) and their subgroups as defined herein, are considered to be useful in the prophylaxis or treatment of a range of conditions or pathological conditions mediated by cyclin-dependent kinases. Examples of such conditions and conditions are indicated above.

The compounds are generally administered to a subject in need of such administration, for example, a human or diseased animal, preferably a human.

The compounds will typically be administered in amounts that are therapeutically or prophylactically useful and are generally non-toxic. However, in certain situations (e.g. in the case of potentially fatal diseases), the benefits of administering a compound of formula (II) may overcome the disadvantages of any toxic effects or side effects, in which case it may be considered desirable to administer the compounds in amounts that are associated with a degree of toxicity.

The compounds may be administered over an extended period to maintain beneficial therapeutic effects or may be administered only for a short time. Alternatively, they may be administered in a pulsatile or continuous manner.

A typical daily dose of the compound may be in the range of from 100 picogram to 100 milligrams per kilogram of body weight, more typically 5 nanogram to 25 milligrams per kilogram of body weight, and more generally 10 nanogram to 15 milligrams per kilogram (eg, 10 nanogram to 10 milligram) per kilogram of body weight, although larger or smaller doses may be given when necessary. Ultimately, the amount of compound administered and the type of composition used will be appropriate to the nature of the disease or physiological condition to be treated and will be at the discretion of the physician.

The compounds of formula (II) may be administered as the sole therapeutic agent or they may be administered in combination therapy with one or more other compounds for treatment of a particular disease state, for example, a neoplastic disease such as a cancer as defined above. Examples of other therapeutic agents which may be administered together (simultaneously or at different time intervals) with the compounds of the formula (II) include but are not limited to topoisomerase inhibitors, alkylating agents, antimetabolites, DNA binders and microtubule inhibitors (tubulin targeting agents), such as cisplatin, cyclophosphamide, doxorubicin, irinotecan, fludarabine, 5FU, taxanes, mitomycin C or radiotherapy. Alternatively, the compounds of formula (II) may be administered in combination therapy with monoclonal antibodies or signal transduction inhibitors. For the case of CDK inhibitors combined with other therapies, the two or more treatments may be administered in dosing regimens that vary individually and through different pathways.

When the compound of formula (II) is administered in combination therapy with one, two, three, four or more other therapeutic agents (preferably one or two, more preferably one), the compounds may be administered simultaneously or sequentially. When administered sequentially, they may be administered at sparsely spaced intervals (for example, over a period of 5-10 minutes) or at longer intervals (for example, 1, 2, 3, 4 or more hours apart, or at even further intervals when necessary), the exact dosage regimen being adapted to the properties of the therapeutic agent (s).

The compounds of formula (II) may also be administered in conjunction with non-chemotherapeutic treatments, such as radiotherapy, photodynamic therapy, gene therapy; surgery and controlled diets.

For use in combination therapy with another chemotherapeutic agent, the compound of formula (II) and one, two, three, four or more other therapeutic agents may be, for example, formulated together in a dosage form containing two, three, four or more therapeutic agents. In one alternative, the individual therapeutic agents may be formulated separately and presented together in the form of a kit, optionally with instructions for their use.

One skilled in the art knows, through his / her common general knowledge, which dosing regimens and combination therapies to use. Diagnostic Methods

Before administration of a compound of formula (II), a patient may be screened to determine whether a disease or condition which the patient suffers from or may suffer from is one that would be amenable to treatment with a compound having activity against cyclin-dependent kinases.

For example, a biological sample harvested from a patient may be analyzed to determine whether a condition or disease, such as cancer, that the patient suffers from or may suffer from is one that is characterized by a genetic abnormality or abnormal protein expression leading to overactivation of CDK or the sensitization of a pathway to normal CDK activity. Examples of such abnormalities that result in activation or sensitization of the CDK2 signal include the positive regulation of cyclin E, (Harwell RM, Mull BB, Porter DC, Keyomarsi K, J Biol Chem. 2004 Mar 26; 279 (13): 12695 -705) or the loss of p21 or p27, or the presence of CDC4 variants (Rajagopalan H, Jallepalli PV, Rago C, Velculescu VE, Kinzler KW, Vogelestein B, Lengauer C. Nature 2004 Mar 4; ): 77-81). The term " positive regulation " includes elevated expression or overexpression, including gene amplification (i.e., multiple gene copies) and expression enhanced by a transcriptional effect, and hyperactivity and activation, including mutation activation. Thus, the patient may undergo a diagnostic test to detect a characteristic marker for the positive regulation of cyclin E, or loss of p21 or p27, or the presence of CDC4 variants. The term diagnosis includes screening. By labeling the applicants include genetic markers including, for example, measuring DNA composition to identify CDC4 mutations. The term "marker" also includes markers that are characteristic of the positive regulation of cyclin E, including enzyme activity, enzyme levels, enzyme status (e.g., phosphorylated or not) and mRNA levels of the above-mentioned proteins.

Tumors with a positive regulation of cyclin E, or loss of p21 or p27 may be particularly sensitive to CDK inhibitors. Preferably, tumors can be screened for positive regulation of cyclin E, or loss of p21 or p27 prior to treatment. Thus, the patient may undergo a diagnostic test to detect a marker characteristic of the positive regulation of cyclin E, or loss of p21 or p27. Diagnostic tests are typically performed on a selected biological sample of tumor biopsy samples, blood samples (isolation and enrichment of deposited tumor cells), fecal biopsies, sputum, chromosome analysis, pleural fluid, peritoneal fluid, or urine.

It has been found, Rajagopalan et al. (Nature 2004 Mar 4; 428 (6978): 77-81), that there were mutations present in CDC4 (also known as Fbw7 or Archipelado) in human endometrial colorectal cancers and endometrial cancers (Spruck et al., Cancer Res. 2002 Aug 15, 62 (16): 4535-9). Identification of individuals having a mutation in CDC4 may mean that the patient would be particularly suitable for treatment with a CDK inhibitor. Preferably, tumors can be screened for the presence of a CDC4 variant prior to treatment. The screening process will typically involve forward sequencing, oligonucleotide microarray analysis, or a mutant specific antibody.

Methods of identifying and analyzing mutations and regulating proteins are known to a person skilled in the art. Screening methods could include, but are not limited to, standard methods, such as polymerase chain reaction (RT-PCR) reverse transcriptase or in situ hybridization.

In RT-PCR screening, the level of mRNA in the tumor is assessed by creating a cDNA copy of the mRNA followed by amplification of the cDNA by PCR. Methods of PCR amplification, primer selection and amplification conditions are known to a person skilled in the art. Nucleic acid manipulations and PCR are performed by standard methods, as described for example in Ausubel, F. M. et al., Eds. Current Protocols in Molecular Biology, 2004, John Wiley & Sons Inc., or Innis, M.A. et al., Eds. PCR Protocols: A Guide to Methods and Applications, 1990, Academic Press, San Diego. Reactions and manipulations involving nucleic acid techniques are also described in Sambrook et al., 2001, 3rd Ed, Molecular Cloning: A Laboratory

Manual, Cold Spring Harbor Laboratory Press. Alternatively a commercially available kit for RT-PCR (for example, Roche Molecular Biochemicals) or methodology as set forth in U.S. Patents 4,666,828; 4,683,202; 4801531; 5192659, 5272057, 5882864, and 6218529.

An example of an in situ hybridization technique for evaluating mRNA expression would be in situ fluorescence hybridization (FISH) (see Angerer, 1987 Meth. Enzymol., 152: 649).

Generally, in situ hybridization comprises the following major steps: (1) fixation of the tissue to be analyzed; (2) pretreatment of the sample to increase the accessibility of the target nucleic acid and to reduce nonspecific binding; (3) hybridizing the nucleic acid mixture with the nucleic acid in the biological framework or tissue; (4) post-hybridization washes to remove the unbound nucleic acid fragments in the hybridization, and (5) detection of the hybridized nucleic acid fragments. Probes used in such applications are typically labeled, for example, with radioisotopes or fluorescent reporters. Preferred probes are sufficiently long, for example, from about 50, 100 or 200 nucleotides to about 1000 or more nucleotides, to allow specific hybridization with the target nucleic acid (s) under strident conditions. Current methods for performing FISH are described in Ausubel, F. M. et al. , eds. Current Protocols in Molecular Biology, 2004, John Wiley & Sons Inc and Fluorescence In Situ Hybridization: Technical Overview of John M. S. Bartlett in Molecular Diagnosis of Cancer, Methods and Protocols, 2nd ed .; ISBN: 1-59259-760-2; March 2004, p. 077-088; Series: Methods in Molecular Medicine.

Alternatively, the protein products expressed from the mRNAs can be analyzed by immunohistochemistry of tumor samples, solid phase immunoassay with microtiter plates, Western blotting, 2-dimensional SDS polyacrylamide gel electrophoresis, ELISA, flow cytometry and others methods known in the art for the detection of specific proteins. Methods of detection would include the use of site-specific antibodies. The skilled person will recognize that all of these well known techniques for detecting positive regulation of cyclin E, or loss of p21 or p27, or detection of CDC4 variants could be applicable in the present case.

Therefore, all of these techniques could also be used to identify tumors particularly suitable for treatment with CDK inhibitors. Patients with mantle cell lymphoma (MCL) could be selected for treatment with a CDK inhibitor using the diagnostic tests outlined herein. MCL is a clinicopathological entity distinct from non-Hodgkin's lymphoma, characterized by proliferation of small to medium lymphocytes with co-expression of CD5 and CD20, an aggressive and incurable clinical course, and translocation t (11; 14) ; q32) frequent. Overexpression of cyclin D1 mRNA found in mantle cell lymphoma (MCL) is a critical diagnostic marker. Yatabe et al. (Blood, 2000 Apr 1; 95 (7): 2253-61) proposed that positivity to cyclin D1 should be included as one of the standard criteria for MCL and that innovative therapies should be explored for this incurable disease based on the new criteria. Jones et al. (J Mol Diagn. 2004 May; 6 (2): 84-9) developed a quantitative, real-time reverse transcription PCR assay for the expression of cyclin D1 (CCND1) to aid in the diagnosis of mantle cell lymphoma (MCL). Howe et al. (Clin Chem 2004 Jan; 50 (1): 80-7) used real-time quantitative RT-PCR to evaluate the expression of cyclin D1 mRNA and determined that quantitative RT-PCR for cyclin D1 mRNA normalized to CD19 mRNA can be used in the diagnosis of MCL in blood, marrow and tissue. Alternatively, breast cancer patients could be selected for treatment with a CDK inhibitor using the diagnostic tests outlined above. Tumor cells generally overexpress cyclin E and cyclin E has been shown to be overexpressed in breast cancer (Harwell et al., Cancer Res, 2000, 60, 481-489). Therefore, breast cancer may in particular be treated with a CDK inhibitor.

Antifungal use

In another aspect, the invention provides the use of the compounds of the formulas (II), (IV), (IVa), (Va), (Vb), (Way) or (VIb) and their subgroups, as defined herein, as agents antifungals.

The compounds may be used in animal medicine (for example, in the treatment of mammals, such as humans), or in the treatment of plants (e.g., in agriculture and horticulture), or as general antifungal agents, for example as preservatives and disinfectants.

In one embodiment, the invention provides a compound of formula (II) and its subgroups, such as formulas (IV), (IVa), (Va), (Vb), (Way) or (VIb) and their subgroups as herein defined for use in the prophylaxis or treatment of a fungal infection in a mammal such as a human. Also provided is the use of a compound of formula (II) and its subgroups, such as formulas (IV), (IVa), (Va), (Vb), (Way) or (VIb) and their subgroups as defined herein for the manufacture of a medicament for use in the prophylaxis or treatment of a fungal infection in a mammal such as a human.

For example, the compounds of formula (II) may be administered to human patients suffering or at risk of infection by topical fungal infections caused by, among other organisms, Candida, Trichophyton,

Microsporum or Epidermophyton, or in mucosal infections caused by Candida albicans (e.g., vaginal thrush and candidiasis). The compounds of formula (II) may also be administered for the treatment or prophylaxis of systemic fungal infections caused, for example, by Candida albicans, Cryptococcus neoformans, Aspergillus flavus, Aspergillus fumigatus, Coccidioidies, Paracoccidioides, Histoplasma or Blastomyces.

In another aspect, the invention provides an antifungal composition for agricultural (including horticultural) use, comprising a compound of the formula (II) and its subgroups, such as of formulas (IV), (V) and (VI) as defined above together with an agriculturally acceptable diluent or carrier. The invention further provides a method of treating an animal (including a mammal such as a human), plant or seed having a fungal infection, which comprises treating said animal, plant or seed, or the location of said plant or seed, with an effective amount of a compound of the formula (II) and its subgroups, such as of formulas (IV), (V) and (VI) as defined above. The invention also provides a method of treating a fungal infection in a plant or seed, which comprises treating the plant or seed with an antifungal effective amount of a fungicidal composition as defined above.

Differential selection assays may be used to select the compounds of the present invention with specificity for non-human CDK enzymes. Compounds that specifically act on the CDK enzymes of eukaryotic pathogens may be used as antifungal or antiparasitic agents. Candida CDK kinase inhibitors, CKSI, may be used in the treatment of candidiasis. Antifungal agents may be used against infections of the above-defined type, or opportunistic infections which usually occur in debilitated and immunosuppressed patients, such as patients with leukemias and lymphomas, persons receiving immunosuppressive therapy, and patients with predisposing conditions such as diabetes mellitus or AIDS , as well as for non-immunosuppressed patients.

Assays described in the art may be used to screen for agents that may be useful for inhibiting at least one fungus implicated in mycoses, such as candidiasis, aspergillosis, mucormycosis, blastomycosis, geotrichosis, cryptococcosis, chromoblastomycosis, coccidioidomycosis, conidiosporosis, histoplasmosis, maduromycosis, rhinosporidiosis , nocardiosis, para-actinomycosis, penicilliosis, monoliase or sporotrichosis. Differential screening assays may be used to identify antifungal agents that may be of therapeutic value in the treatment of aspergillosis using CDK genes cloned from yeast such as Aspergillus fumigatus, Aspergillus flavus, Aspergillus niger, Aspergillus nidulans or Aspergillus terreus, or the fungal infection is mucormycosis, the CDK assay may be derived from yeast, such as Rhizopus arrhizus, Rhizopus oryzae, Absidia corymbifera, Absidia ramosa or Mucorpusillus. Sources of other CDK enzymes include the pathogen Pneumocystis carinii. By way of example, the in vitro evaluation of the antifungal activity of the compounds can be carried out by determining the minimum inhibitory concentration (M.I.C.) which is the concentration of the test compounds in a suitable medium at which growth of the particular microorganism ceases to occur. In practice, a series of agar plates each having the test compound incorporated at a particular concentration is inoculated with a standard culture of, for example, Candida albicans and each plate is then incubated for a suitable period at 37Â ° W. The plates are then examined for the presence or absence of growth of the fungus and the value M.I.C. appropriate. Evaluation of the compounds in vivo can be performed at a series of dose levels by intraperitoneal or intravenous injection or by oral administration to mice that have been inoculated with a fungus e.g. a strain of Candida albicans or Aspergillus flavus. The activity of the compounds can be assessed based on the survival of a group of treated mice after the death of an untreated group of mice. The activity can be measured in terms of the dose level at which the compound provides 50% protection against the lethal effect of the infection (PD50).

For human antifungal use, the compounds may be administered alone or in combination with a pharmaceutical carrier selected according to the intended route of administration and standard pharmaceutical practice. Thus, for example, they may be administered orally, parenterally, intravenously, intramuscularly or subcutaneously via the formulations described above in the section entitled " Pharmaceutical Formulations ".

For oral and parenteral administration in human patients, the daily dosage level of the antifungal compounds of formula (II) may be from 0.01 to 10 mg / kg (in divided doses), depending, inter alia, on the potency of the compounds when administered orally or parenterally. The tablets or capsules of the compounds may contain, for example, from 5 mg to 0.5 g of active compound for single administration or two or more at the same time, as appropriate. In any case, the physician will determine the effective dosage (effective amount) which will be most suitable for a particular patient and will vary with the particular patient's age, weight and response.

Alternatively, the antifungal compounds may be administered in the form of a suppository or pessary, or they may be applied topically in the form of a lotion, solution, cream, ointment or powder for sprinkling. For example, they may be incorporated into a cream consisting of an aqueous emulsion of polyethylene glycols or liquid paraffin; or they may be incorporated at a concentration of 1 to 10% in an ointment consisting of a white wax or white soft paraffin base together with stabilizers and preservatives as may be required.

In addition to the therapeutic uses described above, the antifungal agents developed with the differential selection assays may be used, for example, as preservatives in foodstuffs, food supplements to promote weight gain in livestock, or in disinfectant formulations for the treatment of non- alive, and. for decontamination of equipment and hospital rooms. Similarly, side-by-side comparison of inhibition of a mammalian CDK and an insect CDK, such as the Drosophilia CDK5 gene (Hellmich et al. (1994) FEBS Lett 356: 317-21), will allow selection between the compounds herein of inhibitors which discriminate between the human / mammalian and insect enzymes. Accordingly, the present application describes the use and formulations of the compounds of formula (II) in insecticides, such as for use in controlling insects such as the fruit fly.

In yet another embodiment, certain of the subject CDK inhibitors may be selected based on the specificity of inhibition to plant CDK relative to the mammalian enzyme. For example, a plant CDK can be arranged in a differential screening with one or more of the human enzymes to select those compounds with greater selectivity to inhibit the plant enzyme. Thus, the present invention specifically contemplates formulations of CDK inhibitors subject to agricultural applications, such as in the form of a defoliant or the like.

For agricultural and horticultural purposes, the compounds of formula (II) may be used in the form of a composition formulated as appropriate for the particular intended use and intended purpose. Thus, the compounds may be applied in the form of powders for sprinkling, or granulates, seed treatments, aqueous solutions, dispersions or emulsions, immersion formulations, spray formulations, aerosols or vapors. The compositions may also be provided in the form of dispersible powders, granules or grains, or concentrates for dilution prior to use. Such compositions may contain conventional carriers, diluents or adjuvants as are known and acceptable in agriculture and horticulture, and are manufactured according to the conventional Processes. The compositions may also incorporate other active ingredients, for example, compounds having herbicidal or insecticidal activity or another fungicide. The compounds and compositions may be applied in a number of ways, for example, they may be applied directly to the foliage, stems, branches, seeds or roots of plants or to soil or other growth medium, and these can be used not only to eradicate the disease, but also prophylactically to protect plants or seeds from attack. By way of example, the compositions may contain from 0.01 to 1% by weight of active ingredient. For field use, the likely application rates of the active ingredient may be from 50 to 5000 g / hectare. The invention also contemplates the use of the compounds of the formula (II) and its subgroups, such as formulas (IV), (IVa), (Va), (Vb), (Way) or (VIb) and their subgroups as defined herein in the control of fungi from decomposition of wood and in the treatment of cultivated soils, transplant paddies or water for infusion. Also contemplated by the invention is the use of the compounds of the formula (II) and its subgroups, such as formulas (IV), (IVa), (Va), (Vb), (Way) or (VIb) and their subgroups as here defined to protect stored grains and other non-plant sites from fungal infestation.

EXAMPLES The invention will now be illustrated, but not limited, by reference to the specific embodiments described in the following examples.

In the examples, the compounds prepared were characterized by liquid chromatography and mass spectroscopy (LC-MS) using the system and the operating conditions set forth below. When chlorine is present and a single mass is indicated, the mass indicated for the compound is for 35C1. The two systems were fitted with identical chromatography columns and were set to run under the same operating conditions. The operating conditions used are also described below. In the examples, retention times are given in minutes.

Platform System

System: Waters 2790 / Platform LC

Detector of Esp. Mass: Micromass Platform LC

PDA Detector: Waters 996 PDA

Analytical conditions:

Eluent A: 5% CH 3 CN in 95% H 2 O (0.1% formic acid)

Eluent B: CH 3 CN (0.1% formic acid)

Gradient: 10-95% eluent B

Flow rate: 1.2 mL / min

Column: Synergi 4 pm Max-RP C12, 80A, 50 x 4.6 mm (Phenomenex)

MS Conditions:

Capillary voltage: 3.5 kV

Rated Voltage: 30 V

Source Temperature: 120 ° C

FractionLynx System

System: Waters FractionLynx (dual analytical / prep)

Detector of Esp. Mass: Waters-Micromass ZQ

PDA Detector: Waters 2996 PDA

Analytical conditions:

Eluent A: H 2 O (0.1% formic acid)

Eluent B: CH 3 CN (0.1% formic acid)

Gradient: 5-95% eluent B

Flow rate: 1.5 mL / min

Column: Synergi 4 pm Max-RP C12, 80A, 50 x 4.6 mm (Phenomenex)

MS Conditions:

Capillary voltage: 3.5 kV

Rated Voltage: 30 V

Source Temperature: 120 ° C

Temperature of 300 ° C

Desolation:

LC-MS Analytical System

Several systems were used, as described below, and were fitted and adjusted under similarly stringent operating conditions. The operating conditions used are also described below.

HPLC System: Waters 2795

Detector of Esp. Mass: Micromass Platform LC

PDA Detector: Waters 2996 PDA

Acid Analytical Conditions:

Eluent A: H 2 O (0.1% formic acid)

Eluent B: CH 3 CN (0.1% formic acid)

Gradient: 5-95% eluent B over 3.5 minutes

Flow rate: 0.8 mL / min

Column: Phenomenex Synergi 4 μ MAX-RP 80A, 2.0 x 50 mm

Basic Analytical Conditions:

Eluent A: H 2 O (10 mM NH 4 HCO 3 buffer adjusted to pH = 9.5 with NH 4 OH) Eluent B: CH 3 CN

Gradient: 05-95% eluent B over 3.5 minutes Flow rate: 0.8 mL / min

Column: Thermo Hypersil-Keystone BetaBasic-18 5 æm 2.1 x 50 mm or

Column: Phenomenex Luna C18 (2) 5 pm 2.0 x 50 mm

Polar Analytical Conditions:

Eluent A: H 2 O (0.1% formic acid)

Eluent B: CH 3 CN (0.1% formic acid)

Gradient: 00-50% eluent B over 3 minutes

Flow rate: 0.8 mL / min

Column: or Thermo Hypersil-Keystone HyPurity Aquastar, 5 μ, 2.1 X 5 0 mm

Column: Phenomenex Synergi 4 μ MAX-RP 80A, 2.0 x 50 mm or

Longer Analytical Conditions:

Eluent A: H 2 O (0.1% formic acid)

Eluent B: CH 3 CN (0.1% formic acid)

Gradient: 05-95% eluent B over 15 minutes

Flow rate: 0.4 mL / min

Column: Fenomenex Synergi 4 μ MAX-RP 80A, 2.0 x 150 mm

MS Conditions:

Capillary voltage: 3.6 kV

Rated Voltage: 30 V

Source Temperature: 120 ° C

Scanning Range: 165-700 amu

Ionization Mode: Positive or

Negative Electrospray or Positive Electrospray & Negative

LC-MS System for Mass Co-ordinated Purification

The following preparative chromatography systems may be used to purify the compounds of formula (II). • Hardware:

Waters Fractionlynx System: 2767 Automatic Sampler / Fraction Collector Double 2525 CFO preparative pump (column fluidizer organizer) for selection of RMA column (Waters reagent manager) as compensation pump

Waters ZQ Mass Spectrometer

Waters 2996 Photodiode Array Detector • Software:

Masslynx 4.0 • Columns: 1. Low pH Chromatography: Phenomenex Synergy MAX-RP, 10 μ, 150 x 15 mm (alternatively used the same column type with dimensions 100 x 21.2 μm). 2. High pH chromatography: Fenomenex Luna C18 (2), 10 μ, 100 x 21.2 mm (alternatively used Thermo Hypersil Keystone BetaBasic C 18.5 μ, 100 x 21.2 mm) • Eluents: 1. Chromatography at low pH:

Solvent A: H 2 O + 0.1% formic acid, pH 1.5 Solvent B: CH 3 CN + 0.1% formic acid 2. High pH Chromatography:

Solvent A: H20 + 10mM NH4HCO3 + NH4OH, pH 9.5 Solvent B: CH3CN 3. Compensation solvent: MeOH + 0.1% formic acid (for both types of chromatography)

Before using preparative chromatography to isolate and purify the compounds of the product, analytical LC-MS (see above) may be used first to determine the most appropriate conditions for preparative chromatography. A typical routine is to run an analytical LC-MS using the type of chromatography (low or high pH) most suitable for the structure of the compound. Once the analytical profile shows good chromatography a suitable preparative method of the same type can be chosen. Typical assay conditions for low and high pH chromatography methods are:

Flow rate: 24 mL / min

Gradient: Generally all gradients have an initial step of 0.4 min with 95% A + 5% B. Then, according to the analytical profile, a gradient of 3.6 min is chosen to achieve good separation (eg, from 5% to 50% B for low retention compounds, from 35% to 80% B for medium retention compounds, etc.)

Washing: a washing step of 1 minute is performed at the end of the gradient

Re-equilibrium: a re-equilibration step of 2.1 minutes is performed to prepare the system for the next test

Compensation Flow: 1 mL / min 1 1

Solvent:

All compounds were generally dissolved in 100% MeOH or 100% DMSO • MS test conditions:

Capillary voltage: 3.2 kV

Rated Voltage: 25 V

Source Temperature: 120 ° C

Multiplier: 500 V

Scanning Range: 125-800 amu

Ionization Mode: Positive Electrospray

The starting materials for each of the Examples are commercially available unless otherwise indicated. * = comparative example EXAMPLE 11

4-Amino-1H-pyrazole-3-carboxylic acid phenylamide. 4-Nitro-1H-pyrazole-3-carboxylic acid phenylamide

4-Nitropyrazole-3-carboxylic acid (2.5 g, 15.9 mmol) was added to a stirred solution of aniline (1.6 mL, 17.5 mmol), EDO (3.7 g, 19.1 mmol) and HOBt (2.6 g, 19.1 mmol) in N, N-dimethylformamide (DMF) (25 mL), then stirred at room temperature overnight. The solvent was removed by evaporation under reduced pressure and the residue triturated with ethyl acetate / saturated NaHCO 3 solution. The resulting solid was collected by filtration, washed with water and diethyl ether, then dried under vacuum to give 2.85 g of the title compound (sodium salt) as a yellow / brown solid. (LC / MS: Rt 2.78, [M + H] + 232.95). 1B. 4-Amino-1H-pyrazole-3-carboxylic acid phenylamide

4-nitro-1H-pyrazole-3-carboxylic acid (100 mg, 0.43 mmol) was dissolved in ethanol (5 mL) treated with tin (II) chloride dihydrate (500 mg, 15 mmol), then heated at reflux overnight. The reaction mixture was cooled and evaporated. The residue was partitioned between ethyl acetate and saturated aqueous sodium chloride solution, and the ethyl acetate layer was separated, dried (MgSO 4), filtered and evaporated. The crude product was purified by flash column chromatography eluting with 1: 1 ethyl acetate / petroleum ether, then 5% methanol / dichloromethane. Evaporation of the fractions containing the product followed by preparative LC / MS gave 15 mg of the product as an off-white solid. (LC / MS: Rt 1.40, [M + H] + 202.95). EXAMPLE 2 4-Acetylamino-1H-pyrazole-3-carboxylic acid (4-fluoro-phenyl) -amide 2A. 4-nitro-1H-pyrazole-3-carboxylic acid (4-fluoro-phenyl)

To a stirred solution of 4-fluoroaniline (6.7 mL, 70 mmol), EDO (14.6 g, 76 mmol) was added to a stirred solution of 4-nitropyrazole-3-carboxylic acid (10 g, 63.66 mmol) 4 mmol) and HOBt (10.3 g, 76.4 mmol) in DMF (25 mL), then stirred at room temperature overnight. The solvent was removed by evaporation under reduced pressure and the residue triturated with ethyl acetate / brine. The resulting yellow solid was collected by filtration, washed with 2M hydrochloric acid, then dried under vacuum to give 15.5 g of the title compound. (LC / MS: Rt 2.92 [M + H] + 250.89). 2B. 4-Amino-1H-pyrazole-3-carboxylic acid (4-fluoro-phenyl)

4-nitro-1H-pyrazole-3-carboxylic acid (4-fluorophenyl) -amide (15 g) was dissolved in 200 mL of ethanol, treated with 1.5 g of 10% palladium on charcoal under a nitrogen atmosphere , then hydrogenated at room temperature and pressure overnight. The catalyst was removed by filtration through Celite and the filtrate evaporated. The crude product was dissolved in acetone / water (100 mL: 100 mL) and after slow evaporation of acetone the product was collected by filtration as a tan crystalline solid (8.1 g). (LC / MS: Rt 1.58, [M + H] + 220.95). 2C. 4-Acetylamino-1 H -pyrazole-3-carboxylic acid (4-fluoro-phenyl)

4-Amino-1H-pyrazole-3-carboxylic acid (4-fluorophenyl) -amide (500 mg, 2.27 mmol) was dissolved in 5 mL of pyridine, treated with acetic anhydride (240 μL, 2.5 mmol) , then stirred at room temperature overnight. The solvent was removed by evaporation, then dichloromethane (20 mL) and 2M hydrochloric acid (20 mL) were added. The undissolved solid was collected by filtration, washed with more dichloromethane and water, then dried under vacuum. The product was isolated as an off-white solid (275 mg). (LC / MS: Rt 2.96, [M + H] + 262.91). EXAMPLE 3 (4-Fluoro-phenyl) -amide 4- [2,2,2-trifluoro-acetylamino) -1H-pyrazole-3-carboxylic acid

4-Amino-1H-pyrazole-3-carboxylic acid (4-fluorophenyl) -amide (Example 2B) (500 mg, 2.27 mmol) was dissolved in 5 mL of pyridine, treated with trifluoroacetic anhydride (320 μL, 2 , 5 mmol) then stirred at room temperature overnight. The solvent was removed by evaporation, the residue was partitioned between ethyl acetate (50 mL) and 2M hydrochloric acid (50 mL), and the ethyl acetate layer was separated, washed with brine (50 mL). mL), dried (MgSO4), filtered and evaporated to give 560 mg of product as a brown solid. (LC / MS: [M + H] + 317). EXAMPLE 4 4 - [(5-Oxo-pyrrolidine-2-carbonyl) -amino] -1H-pyrazole-3-carboxylic acid (4-fluoro-phenyl)

To a stirred solution of 4-amino-1H-pyrazole-3-carboxylic acid (4-fluorophenyl) -amide (Example 2B) (50 mg, 0.23 mmol), EDAC (52 mg, 27 mmol) and HOBt (37 mg, 0.27 mmol) in 5 mL of DMF was added 2-oxoproline (33 mg, 0.25 mmol), and the mixture was then left at room temperature overnight. The reaction mixture was evaporated and the residue purified by preparative LC / MS, to give 24 mg of the product as a white solid. (LC / MS: Rt 2.27 [M + H] + 332). EXAMPLE 5 4-Phenylacetylamino-1 H -pyrazole-3-carboxylic acid (4-fluoro-phenyl)

The reaction was run in a manner analogous to Example 4 but using phenylacetic acid (34 mg, 0.23 mmol) as the starting material. The title compound (14 mg) was isolated as a white solid. (LC / MS: Rt 3.24 [M + H] + 339). EXAMPLE 6 4- (4-Fluoro-phenyl) -amide-4- (2-1H-indol-3-yl-acetylamino) -1H-pyrazole-3-carboxylic acid

The reaction was performed in a manner analogous to Example 4, but using indole-3-acetic acid (44 mg, 0.23 mmol) as the starting material. The title product (14 mg) was isolated as a white solid. (LC / MS: Rt 3.05 [M + H] + 378). EXAMPLE 7 4- (2-Benzenesulfonyl-acetylamino-1H-pyrazole-3-carboxylic acid (4-fluorophenyl)

The reaction was performed in a manner analogous to Example 4, but using 2- (phenylsulfonyl) acetic acid (50 mg, 0.23 mmol) as the starting material. The title compound (29 mg) was isolated as a white solid. (LC / MS: Rt 3.00 [M + H] + 403). EXAMPLE 8 4- [2- (5-Amino-Tetrazol-1-yl) -acetylamino] -1H-pyrazole-3-carboxylic acid {4-

The reaction was performed in a manner analogous to Example 4, but 5-aminotetrazole-1-acetic acid (36 mg, 0.23 mmol) was used as the starting material. The title compound (23 mg) was isolated as a white solid. (LC / MS: Rt 2.37 [M + H] + 346). EXAMPLE 9 N- [3- (4-Fluoro-phenylcarbamoyl) -1H-pyrazol-4-yl] -6-hydroxy-nicotinamide

The reaction was performed in a manner analogous to Example 4, but using 6-hydroxynicotinic acid (38 mg, 0.23 mmol) as the starting material. The title compound (17 mg) was isolated as a white solid. (LC / MS: Rt 2.32 [M + H] + 342). EXAMPLE 10 * (4-Fluorophenyl) -amide [4- [3- (4-chloro-phenyl) -propionylamino] -1H-pyrazole-3-

The reaction was performed in a manner analogous to Example 4, but using 3- (4-chlorophenyl) propionic acid (46 mg, 0.23 mmol) as the starting material. The title compound (40 mg) was isolated as a white solid. (LC / MS: Rt 3.60 [M + H] + 388). EXAMPLE 11 4- (3-4H- [1,2,4] Triazol-3-yl-propionylamino] -1H-pyrazole-3-carboxylic acid (4-

The reaction was run in a manner analogous to Example 4, but using 3-triazol-3-ylpropionic acid (36 mg, 0.23 mmol) as the starting material. The title compound (18 mg) was isolated as a white solid. (LC / MS: Rt 2.39 [M + H] + 344). EXAMPLE 12 4- [2- (1-Methyl-1H-indol-3-yl) -acetylamino] -1H-pyrazole-3-carboxylic acid (4-fluoro-phenyl)

The reaction was performed in a manner analogous to Example 4, but using N-methylindole-3-acetic acid (48 mg, 0.23 mmol) as the starting material. The title compound (20 mg) was isolated as a white solid. (LC / MS: Rt 3.34 [M + H] + 392). EXAMPLE 13 4- (4-Fluoro-phenyl) -amide [4 - [(1-hydroxy-cyclopropanecarbonyl) -amino] -1H-pyrazole-3-

The reaction was performed in a manner analogous to Example 4, but using 1-hydroxycyclopropanecarboxylic acid (26 mg, 0.23 mmol) as the starting material. The title compound (24 mg) was isolated as a white solid. (LC / MS: Rt 2.55 [M + H] + 305). EXAMPLE 14 1-Acetyl-piperidine-4-carboxylic acid [3- (4-fluoro-phenylcarbamoyl) -1H-pyrazol-4-yl]

The reaction was run in a manner analogous to Example 4, but using N-acetylpiperidine-acetic acid (43 mg, 0.23 mmol) as the starting material. The title compound (19 mg) was isolated as a white solid. (LC / MS: rt 2.49 [M + H] + 374). EXAMPLE 15 4- [3- (4-Methyl-piperazin-1-yl) -propionylamino] -1H-pyrazole-3-carboxylic acid (4-fluoro-phenyl)

The reaction was performed in a manner analogous to Example 4, but using 4-N-methylpiperazine-1-N-propionic acid (31 mg, 0.23 mmol) as the starting material. The title compound (19 mg) was isolated as a white solid. (LC / MS: Rt 1.77 [M + H] + 375). EXAMPLE 16 4- (2-1H-Imidazol-4-yl-acetylamino) -1H-pyrazole-3-carboxylic acid (4-

The reaction was run in a manner analogous to Example 4, but using imidazole-4-acetic acid (32 mg, 0.23 mmol) as the starting material. The title compound (35 mg) was isolated as a white solid. (LC / MS: Rt 1.82 [M + H] + 329). EXAMPLE 17 * Propionylamino) -1H-pyrazole-3-carboxylic acid (4-fluorophenyl)

The reaction was run in a manner analogous to Example 4, but using 3-morpholin-4-yl-propionic acid (40 mg, 0.23 mmol) as the starting material. The title compound (15 mg) was isolated as a white solid. (LC / MS: Rt 1.84 [M + H] + 362). EXAMPLE 18 4- (4-Fluorophenyl) -amide [4- (3-piperidin-1-yl-propionylamino) -1H-pyrazole-3-carboxylic acid

The reaction was performed in a manner analogous to Example 4, but using 3-piperidin-4-yl-propionic acid (39 mg, 0.23 mmol) as the starting material. The title compound (19 mg) was isolated as a white solid. (LC / MS: Rt 1.92 [M + H] + 360). EXAMPLE 19 4-Cyclohexylamino-1 H -pyrazole-3-carboxylic acid (4-fluoro-phenyl)

To a solution of 4-amino-1H-pyrazole-3-carboxylic acid (4-fluoro-phenyl) -amide (200 mg, 1 mmol) and cyclohexanone (107 mg, 1.1 mmol) in dichloromethane ml) were added 3Å molecular sieves (1 g) and sodium triacetoxyborohydride (315 mg, 1.5 mmol), and the mixture was then stirred at room temperature over the weekend. The reaction mixture was filtered through Celite®, diluted with ethyl acetate, washed with brine, dried (MgSO4) and evaporated to give 48 mg of the product as a gray gum. (LC / MS: Rt 2.95, [M + H] + 285). (4-Fluorophenyl) -amide] 4-isopropylamino-1H-pyrazole-3-carboxylic acid

The title compound was prepared in a manner analogous to Example 19, but using acetone instead of cyclohexanone. (LC / MS: Rt 2.08, [M + H] + 245). EXAMPLE 21 * (4-Fluorophenyl) -amide * 4- (2-hydroxy-1-methyl-ethylamino) -1H-pyrazole-3-

The compound was prepared in a manner analogous to Example 19, but using hydroxyacetone instead of cyclohexanone. NMR (400MHz, D 6 -DMSO): 9.9 (1H, br s), 7.8 (2H, dd), 7.3 (1H, s), 7.15 (2H, t) 15 (1H, d), 4.7 (1H, br s), 3.4 (2H, m), 3.2 (1H, m), 1.1 (3H, d). EXAMPLE 22 4- (1-Ethyl-propylamino) -1H-pyrazole-3-carboxylic acid (4-fluoro-phenyl)

The compound was prepared in a manner analogous to Example 19, but using 3-pentanone instead of cyclohexanone. NMR Î'(400MHz, D6-DMSO): 12.85 (1H, br s), 9.9 (1H, br s), 7.8 (2H, br.), 7.3 (1H, s), (1H, m), 1.5 (4H, m), 3.2 (1H, m), 0.9 (1H, 6H, t). EXAMPLE 23 4- (3-Chloro-pyrazin-2-ylamino) -1H-pyrazole-3-carboxylic acid (4-fluoro-phenyl)

A mixture of 4-amino-1H-pyrazole-3-carboxylic acid (4-fluoro-phenyl) -amide (50 mg, 0.23 mmol) and 2,3-dichloropyrazine (140 mg, 0.92 mmol) was heated at 150 ° C (50W) for 20 minutes on a CEM Discover ™ microwave synthesizer. The crude reaction mixture was purified by flash column chromatography eluting with ethyl acetate / hexane (1: 3 then 1: 2). The product-containing fractions were combined and evaporated to give 15 mg of the title compound as a white solid. (LC / MS: Rt 4.06 M + H] + 332). EXAMPLE 2 4- (Pyrazin-2-ylamino) -1H-pyrazole-3-carboxylic acid (4-fluoro-phenyl)

The compound was prepared in a manner analogous to Example 23, but using 2-chloropyrazine instead of 2,3-dichloropyrazine. (LC / MS: Rt 3.28 [M + H] + 299). EXAMPLE 25 Synthesis of 4- (2-Methoxy-benzoylamino) -1H-pyrazole-3-carboxylic acid (4-Fluoro-phenyl)

2-Methoxy-benzoic acid (38 mg, 0.25 mmol) was added to a solution of 4-amino-1H-pyrazole-3-carboxylic acid (4-fluoro-phenyl) -amide (50 mg, 23 mmol), EDO (53 mg, 0.27 mmol) and HOBt (37 mg, 0.27 mmol) in DMF (5 mL). The reaction mixture was stirred at room temperature for 24 hours. The solvent was removed under reduced pressure. The residue was purified by preparative LC / MS and, after evaporation of product-containing fractions, afforded the product as a pink solid (12 mg, 15%). (LC / MS: Rt 4.00, [M + H] + 354.67). EXAMPLE 26 * Synthesis of 4-benzoylamino-1 H -pyrazole-3-carboxylic acid (4-Fluoro-phenyl)

The experiment was performed in an analogous manner to Example 25 using benzoic acid (31 mg, 0.25 mmol) as the starting acid. The product was isolated as a pink solid (26 mg, 35%). (LC / MS: Rt 3.96, [M + H] + 324.65). EXAMPLE 27 Synthesis of 4- (cyclohexanecarbonylamino-1H-pyrazole-3-carboxylic acid (4-fluoro-phenyl)

The experiment was performed in an analogous manner to Example 25 using cyclohexanecarboxylic acid (32 mg, 0.25 mmol) as the starting acid. The product was isolated as a pink solid (28 mg, 37%). (LC / MS: Rt 4.16, [M + H] + 330.70). EXAMPLE 28 Synthesis of 4 - [(1-Methyl-cyclopropanecarbonyl) -amino] -1H-pyrazole-3-carboxylic acid (4-Fluoro-phenyl)

The experiment was performed in an analogous manner to Example 25 using 1-methyl-cyclopropanecarboxylic acid (25 mg, 0.25 mmol) as the starting acid. The product was isolated as a pink solid (24 mg, 35%). (LC / MS: Rt 3.72, [M + H] + 302.68). EXAMPLE 29 Synthesis of 4- (2-Hydroxyacetylamino) -1H-pyrazole-3-carboxylic acid (4-Fluoro-phenyl)

The experiment was performed in an analogous manner to Example 25 using hydroxy acetic acid (19 mg, 0.25 mmol) as the starting acid. The product was isolated as a white solid (26 mg, 41%). (LC / MS: Rt 2.65, [M + H] + 278.61). EXAMPLE 30 Synthesis of 4- (2,2-dimethyl-propionylamino) -1H-pyrazole-3-carboxylic acid (4-Fluoro-phenyl)

The experiment was performed in an analogous manner to Example 25 using 2,2-dimethyl-propionic acid (26 mg, 0.25 mmol) as the starting acid. The product was isolated as a pink solid (21 mg, 30%). (LC / MS: Rt 3.83, [M + H] + 304.68). EXAMPLE 31 Synthesis of 4- (3-Hydroxy-propionylamino) -1H-pyrazole-3-carboxylic acid (4-Fluoro-phenyl)

The experiment was performed in a manner analogous to Example 25 using 3-hydroxy-propionic acid (75.1 mg, 0.25 mmol) as the starting acid. The product was isolated as a beige solid (5 mg, 8%). (LC / MS: Rt 2.58, [M + H] + 292.65). EXAMPLE 32 * Synthesis of 4- (2-fluoro-benzoylamino) -1H-pyrazole-3-carboxylic acid (4-fluorophenyl)

2-Fluorobenzoic acid (36 mg, 0.25 mmol) was added to a solution of 4-amino-1 H -pyrazole-3-carboxylic acid (4-fluoro-phenyl) -amide (50 mg, 0.23 mmol ), EDO (53 mg, 0.27 mmol) and HOBt (37 mg, 0.27 mmol) in DMSO (1 mL). The reaction mixture was stirred at room temperature for 24 hours and purified by preparative LC / MS. Evaporation of the fractions containing the product gave the product as a white solid (15 mg, 19%). (LC / MS: Rt 3.91, (M + H) +, 342.66) EXAMPLE 33 Synthesis of 4- (3-fluoro-benzoylamino) -1H-pyrazole-3- carboxylic acid

The experiment was performed in a manner analogous to that of Example 32 using 3-fluorobenzoic acid (36 mg, 0.25 mmol) as the starting acid. The product was isolated as a white solid (19 mg, 24%). (LC / MS: Rt 4.03, [M + H] + 342.67). EXAMPLE 34 * Synthesis of 4- (3-Methoxy-benzoylamino) -1H-pyrazole-3-carboxylic acid (4-Fluoro-phenyl)

The experiment was carried out in a manner analogous to

Example 32 using 3-methoxy-benzoic acid (39 mg, 0.25 mmol) as the starting acid. The product was isolated as a white solid (20 mg, 25%). (LC / MS: Rt 3.97, [M + H] + 354.68). EXAMPLE 35 * Synthesis of 4- (2-nitro-benzoylamino) -1H-pyrazole-3-carboxylic acid (4-fluorophenyl)

The experiment was carried out in a manner analogous to

Example 32 using 2-nitrobenzoic acid (43 mg, 0.25 mmol) as the starting acid. The product was isolated as a white solid (17 mg, 20%). (LC / MS: Rt 3.67, [M + H] + 369.66). EXAMPLE 36 * Synthesis of 4- (4-nitrobenzoylamino) -1H-pyrazole-3-carboxylic acid (4-fluorophenyl)

The experiment was carried out in a manner analogous to

Example 32 using 4-nitrobenzoic acid (43 mg, 0.25 mmol) as the starting acid. The product was isolated as a white solid (15 mg, 18%). (LC / MS: Rt 3.98, [M + H] + 369.63). EXAMPLE 37 Synthesis of 4 - [(3-methyl-furan-2-carbonyl) -amino] -1H-pyrazole-3-carboxylic acid (4-Fluoro-phenyl)

The experiment was carried out in a manner analogous to

Example 32 using 3-methyl-2-furoic acid (32 mg, 0.25 mmol) as the starting acid. The product was isolated as a white solid (15 mg, 20%). (LC / MS: Rt 3.86, [M + H] + 328.68). EXAMPLE 38 * Synthesis of 4 - [(furan-2-carbonyl) -amino] -1H-pyrazole-3-carboxylic acid (4-Fluoro-phenyl)

The experiment was carried out in a manner analogous to

Example 32 using 2-furoic acid (29 mg, 0.25 mmol) as the starting acid. The product was isolated as a white solid (18 mg, 25%). (LC / MS: Rt 3.56, [M + H] + 314.64). EXAMPLE 39 Synthesis of 4 - [(3H-imidazole-4-carbonyl) -amino] -1H-pyrazole-3-carboxylic acid (4-fluorophenyl)

The experiment was carried out in a manner analogous to

Example 32 using 1 H -imidazole-4-carboxylic acid (29 mg, 0.25 mmol) as the starting acid. The product was isolated as a white solid (16 mg, 22%). (LC / MS: Rt 2.59, [M + H] + 314.65). EXAMPLE 40 * Synthesis of 4- (4-Fluoro-benzoylamino) -1H-pyrazole-3-carboxylic acid (4-fluorophenyl)

The experiment was carried out in a manner analogous to

Example 32 using 4-fluorobenzoic acid (36 mg, 0.25 mmol) as the starting acid. The product was isolated as a cream colored solid (23 mg, 29%). (LC / MS: Rt 4.00, [M + H] + 342.67). EXAMPLE 41 * Synthesis of 4- (2,6-Difluoro-benzoylamino-1H-pyrazole-3-carboxylic acid (4-Fluoro-phenyl)

The experiment was carried out in a manner analogous to

Example 32 using 2,6-difluorobenzoic acid (40 mg, 0.25 mmol) as the starting acid. The product was isolated as a cream colored solid (25 mg, 30%). (LC / MS: Rt 3.76, [M + H] + 366.66). EXAMPLE 42 * Synthesis of 4- (3-nitro-benzoylamino) -1H-pyrazole-3-carboxylic acid (4-fluorophenyl)

The experiment was carried out in a manner analogous to

Example 32 using 3-nitrobenzoic acid (43 mg, 0.25 mmol) as the starting acid. The product was isolated as a cream colored solid (15 mg, 18%). (LC / MS: Rt 3.94, [M + H] + 369.65). EXAMPLE 43 Synthesis of 1H-indole-3-carboxylic acid [3- (4-Fluoro-phenylcarbamoyl) -1H-pyrazol-4-yl]

The experiment was carried out in a manner analogous to

Example 32 using indole-3-carboxylic acid (41 mg, 0.25 mmol) as the starting acid. The product was isolated as a rust-colored solid (14 mg, 17%). (LC / MS: Rt 3.60, [M + H] + 363.66). EXAMPLE 44 Synthesis of 4- (4-hydroxymethyl-benzoylamino) -1H-pyrazole-3-carboxylic acid (4-Fluoro-phenyl)

The experiment was performed in an analogous manner to Example 32 using 4-hydroxymethylbenzoic acid (39 mg, 0.25 mmol) as the starting acid. The product was isolated as a white solid (19 mg, 23%). (LC / MS: Rt 3.12, [M + H] + 354.68). EXAMPLE 45 * Synthesis of 4- (3-methyl-benzoylamino) -1H-pyrazole-3-carboxylic acid (4-fluorophenyl)

The experiment was carried out in a manner analogous to

Example 32 using 3-methylbenzoic acid (35 mg, 0.25 mmol) as the starting acid. The product was isolated as an off-white solid (21 mg, 27%). (LC / MS: Rt 4.13, [M + H] + 338, 71). EXAMPLE 46 * Synthesis of 4- (2-methyl-benzoylamino) -1H-pyrazole-3-carboxylic acid (4-fluorophenyl)

The experiment was carried out in a manner analogous to

Example 32 using 2-methylbenzoic acid (35 mg, 0.25 mmol) as the starting acid. The product was isolated as an off-white solid (20 mg, 26%). (LC / MS: Rt 4.05, [M + H] + 338.69). EXAMPLE 47 Synthesis of 4- (4-methylbenzoylamino) -1H-pyrazole-3-carboxylic acid (4-fluorophenyl)

The experiment was performed in a manner analogous to that of Example 32 using 4-methylbenzoic acid (35 mg, 0.25 mmol) as the starting acid. The product was isolated as an off-white solid (19 mg, 24%). (LC / MS: Rt 4.16, [M + H] + 338.70). EXAMPLE 48 Synthesis of 4 - [(2-methyl-thiophene-3-carbonyl) -amino] -1H-pyrazole-3-carboxylic acid (4-Fluoro-phenyl)

2-Methyl-3-thiophenecarboxylic acid (36 mg, 0.25 mmol) was added to a solution of 4-amino-1H-pyrazole-3-carboxylic acid (4-fluoro-phenyl) -amide (Example 2B) (50 mg, 0.23 mmol), EDO (53 mg, 0.27 mmol) and HOBt (37 mg, 0.27 mmol) in DMSO (1 mL). The reaction mixture was stirred at room temperature for 24 hours. The reaction mixture was added dropwise to water (30 mL) and the resultant solid was collected by filtration, washed with water and dried by suction. The title compound was obtained as a beige solid (15 mg, 19%). (LC / MS: Rt 4.08, [M + H] + 344.67). EXAMPLE 49 Synthesis of quinoline-2-carboxylic acid [3- (4-Fluoro-phenylcarbamoyl) -1H-pyrazol-4-yl] -amide

The experiment was performed in an analogous manner to Example 48 using quinaldic acid (44 mg, 0.25 mmol) as the starting acid. The product was isolated as a brown solid (16 mg, 19%). (LC / MS: Rt 4.29, [M + H] + 375.66). EXAMPLE 50 Synthesis of 4 - [(Thiophene-3-carbonyl) -amino] -1H-pyrazole-3-carboxylic acid (4-Fluoro-phenyl)

The experiment was performed in an analogous manner to Example 48 using thiophene-3-carboxylic acid (33 mg, 0.25 mmol) as the starting acid. The product was isolated as a beige solid (15 mg, 20%). (LC / MS: Rt 3.77, [M + H] + 330.61). EXAMPLE 51 4- (4-Fluorophenyl) -amide [4- (2-fluoro-3-methoxybenzoylamino) -1H-pyrazole-3-carboxylic acid

2-fluoro-3-methoxybenzoic acid (0.047 g, 0.28 mmol), 4-amino-1H-pyrazole-3-carboxylic acid (4-fluoro-phenyl) -amide (Example 2B) (0.055 g, 25 mmol), EDO (0.58 g, 0.30 mmol) and HOBt (0.041 g, 0.30 mmol) were stirred at room temperature in DMSO (1.25 mL) for 5 hours. The reaction mixture was poured into water (30 mL) and the resultant solid was collected by filtration and dried in a vacuum oven to give the title compound as a gray solid (0.058 g, 63%). (LC / MS: Rt 3.99, [MH] + 372.98). EXAMPLE 52 Synthesis of 4- [2- (2-pyrrolidin-1-yl-ethoxy) -benzoylamino] -1H-pyrazole-3-carboxylic acid 4-fluorophenylamide 52A 2- (2-pyrrolidin-1 ethoxy) -benzoic acid

Diisopropyl azodicarboxylate (0.404 g, 2 mmol) was added dropwise to a solution of triphenylphosphine (0.524 g, 2 mmol) in THF (10 mL). Methyl salicylate (0.304 g, 2 mmol) was added dropwise, and the resulting mixture was stirred at room temperature for 1 hour. 1,2-Hydroxyethylpyrrolidine (0.230 g, 2 mmol) was added dropwise and the reaction mixture was allowed to stir at room temperature for an additional 1.5 hours. The resulting solution was reduced in vacuo and flash column chromatographed, eluting with hexane: ethyl acetate (5: 1, 1: 1) then ethyl acetate: methanol (4: 1) to give the product as an oil clear yellow (0.104 g, 21%). (LC / MS: Rt 0.69, 1.62, [MH] + 250.02). 52B 4- [2- (2-Pyrrolidin-1-yl-ethoxyl-benzoylamino] -1H-pyrazole-3-carboxylic acid 4-fluorophenylamide

2- (2-Pyrrolidin-1-yl-ethoxy) -benzoic acid methyl ester (0.104 g, 0.42 mmol) was treated with 2M aqueous NaOH (20 mL) and water (20 mL). The reaction mixture was stirred at room temperature for 20 hours, then reduced in vacuo and azeotroped with toluene (3 x 5 mL). Water (50 mL) was added and the mixture adjusted to pH 5 using 1 aqu aqueous HCl. The resulting solution was reduced in vacuo and azeotroped with toluene (3 x 5 mL) to give a white solid, which was combined with 4-amino-1 H -pyrazole-3-carboxylic acid (4-fluoro-phenyl) (0.055 g, 0.25 mmol), EDC (0.058 g, 0.3 mmol) and HOBt (0.041 g, 0.3 mmol) and stirred at room temperature in DMSO (3 mL) for 20 hours. The reaction mixture was poured into water (30 mL) and the resulting solid collected by filtration and dried in a vacuum oven to give the title compound as a gray solid (0.015 g, 14%). (LC / MS: Rt 2.18, [MH] + 438.06). EXAMPLE 53 Synthesis of 4- (2,6-difluoro-benzylamino) -1 H -pyrazole-3-carboxylic acid (1-methylpiperidin-4-yl)

A mixture of 4- (2,6-difluoro-benzoylamino) -1H-pyrazole-3-carboxylic acid (134 mg, 0.50 mmol), 4-amino-4-methylpiperidine (50.0 μL, 0.45 mmol ), EDAC (104 mg, 0.54 mmol) and HOBt (73.0 mg, 0.54 mmol) in DMF (3 mL) was stirred at room temperature for 16 hours. The mixture was reduced in vacuo, the residue taken up in AcOEt and washed successively with saturated aqueous sodium bicarbonate, water and brine. The organic portion was dried (MgSCP) and reduced in vacuo to give 4- (2,6-difluoro-benzoylamino) -1H-pyrazole-3-carboxylic acid (1-methyl-piperidin-4-yl) -amide as a white solid (113 mg, 69%). (LC / MS: Rt 2.52, [M + H] + 364.19). EXAMPLE 54 Synthesis of 4- (Cyclohexylmethylamino) -1H-pyrazole-3-carboxylic acid (4-Fluoro-phenyl)

This compound was prepared analogously to the compound of Example 19 by successive reductive alkylations using first cyclohexanone and then formaldehyde. (LC / MS: Rt 2.77 [MH] + 316.71). EXAMPLE 55 4- (Pyridin-2-ylamino) -1H-pyrazole-3-carboxylic acid (4-fluoro-phenyl)

The title compound was prepared in a manner analogous to the compound of Example 23. (LC / MS: Rt 2.07 [MH] +298.03). EXAMPLES 56-81

Following the procedures described in the previous examples or analogous methods thereto, or carrying out chemical transformations using the compounds described in the above examples and methods of synthesis well known to the skilled person, the compounds set forth in Table 3 were prepared.

EXAMPLE 82 4 - [(4-Amino-1-methyl-1H-imidazole-2-carbonyl) -amino] -1H-pyrazole-3-carboxylic acid (4-fluoro-phenyl)

Trifluoroacetic acid (200 μL) was added to a stirred suspension of {2- [3- (4-fluoro-phenylcarbamoyl) -1H-pyrazol-4-ylcarbamoyl] -1-methyl- imidazol-4-yl} -carbamic acid tert-butyl ester (30 mg) in dichloromethane (5 mL), then stirred at room temperature for 2 hours. The solvent was evaporated, then reevaporated with toluene (2 x 10 mL). The residue was triturated with diethyl ether and the resulting solid collected by filtration. The solid was washed with diethyl ether, then dried under vacuum to give 4 - [(4-amino-1-methyl-1H-imidazole-2-carbonyl) -piperidine-4-carboxylic acid (4-fluoro- amino] -1H-pyrazole-3-carboxylic acid as an off-white solid. (LC / MS: [M + H] + 343.72). EXAMPLE 83 Synthesis of 4 - {[4- (2,6-Difluoro-benzoylamino) -1H-pyrazole-3-carbonyl] -amino} -cyclohexanecarboxylic acid 83A. 6-difluorobenzoylamino) -1H-pyrazole-3-carbonyl] -amino} -cyclohexanecarboxylic acid

Thionyl chloride (0.32 mL, 4 mmol) was slowly added to a mixture of 4-aminocyclohexanecarboxylic acid (572 mg, 4.00 mmol) in EtOH (10 mL) and stirred at room temperature for 16 hours. The mixture was reduced in vacuo by subjecting the azeotropic evaporation with toluene to give the corresponding ethyl ester (650 mg) as a pale solid. The mixture of ethyl ester (103 mg, 0.60 mmol), 4- (2,6-difluoro-benzoylamino) -1H-pyrazole-3-carboxylic acid (134 mg, 0.50 mmol), EDC (115 mg, 0.60 mmol) and HOBt (81 mg, 0.60 mmol) in DMF (5 mL) was stirred at room temperature for 16 hours. The mixture was reduced in vacuo, the residue taken up in AcOEt and washed successively with saturated aqueous sodium bicarbonate, water and brine. The organic portion was dried (MgSO4) and reduced in vacuo to give 4 - {[4- (2,6-difluoro-benzoylamino) -1H-pyrazole-3-carbonyl] -amino} -cyclohexanecarboxylic acid ethyl ester ( 112 mg). 83B. 4 - {[4- (2,6-Difluoro-benzoylamino-1H-pyrazole-3-carbonyl] -amino} -cyclohexanecarboxylic acid

A mixture of the ester (45 mg) (from 83A) in MeOH (2.5 mL) and 2M aqueous NaOH (2.5 mL) was stirred at room temperature for 16 hours. The volatiles were removed in vacuo, water (10 mL) was added and the mixture adjusted to pH 5 using 1 aqu aqueous HCl. The precipitate formed was collected by filtration and purified by column chromatography using EtOAc / MeOH (1: 0-9: 1) to give 4 - {[4- (2,6-difluorobenzoylamino) 3-carbonyl] -amino} -cyclohexanecarboxylic acid methyl ester (11 mg) as a white solid and cis / trans isomer mixture. (LC / MS: Rt 2.78 and 2.96, [M + H] + 393.09). EXAMPLES 84 - 152

General Procedure A

Preparation of Amide from Pyrazole Carboxylic Acid

A mixture of the appropriate benzoylamino-17β-pyrazole-3-carboxylic acid (0.50 mmol), EDAC (104 mg, 0.54 mmol), HOBt (73.0 mg, 0.54 mmol) and the corresponding amine (0.45 mmol) in DMF (3 mL) was stirred at room temperature for 16 hours. The mixture was reduced in vacuo, the residue taken up in AcOEt and washed successively with saturated aqueous sodium bicarbonate, water and brine. The organic portion was dried (MgSO4) and reduced in vacuo to give the desired product.

General Process B

Preparation of Amide from Amino-Pyrazole

To a stirred solution of the appropriate 4-amino-1H-pyrazole-3-carboxylic acid amide (0.23 mmol), EDAC (52 mg, 0.27 mmol) and HOBt (37 mg, , 27 mmol) in 5 mL of N, N-dimethylformamide was added the corresponding carboxylic acid (0.25 mmol) and the mixture was then left at room temperature overnight. The mixture

The reaction was evaporated and the residue purified by preparative LC / MS to give the product.

General Process C

Deprotection of Piperidine Endocyclic Nitrogen by Removal of tert-Butoxycarbonyl Group

A product of Process A or Process B containing a piperidine group having a N-tert-butoxycarbonyl (t-Boc) protecting group (40 mg) was treated with ethyl acetate / saturated HCl, and stirred at room temperature for 1 hour . A solid precipitated from the reaction mixture, which was filtered, washed with ether and then dried to give 25 mg of product (LC / MS: [M + H] + 364).

Process L

Preparation of Amine Starting Materials The following method was used to prepare the following amines: 4-thiomorpholine-4-yl-cyclohexylamine; 4- (1,1-dioxo-thiomorpholin-4-yl) -cyclohexylamine; N- (tetrahydro-pyran-4-yl) -cyclohexane-1,4-diamine; 4- (4-methyl-piperazin-1-yl) -cyclohexylamine; 1'-methyl- [1,4 '] bipiperidinyl-4-ylamine; and 4-morpholin-4-yl-cyclohexylamine.

A solution of N-4-Boc-aminocyclohexanone (0.5 g, 2.3 mmol) in THF (10 mL) was treated with the appropriate amine, e.g. thiomorpholine (0.236 g, 2.3 mmol), and sodium triacetoxyborohydride (0.715 g, 2.76 mmol) and acetic acid (0.182 mL). The reaction was stirred overnight at room temperature, then diluted with CH2 Cl2 and washed with saturated sodium carbonate. The organic layer was dried over MgSO4 and evaporated to give a white solid which was used in the next step without further purification. The white solid was treated with saturated HCl / EtOAc, stirred at room temperature for 1 hour, evaporated to dryness and then reevaporated with toluene. The resulting amines were isolated as the hydrochloride salt. (LC / MS: Rt 1.75, [M + H] + 201).

Following General Processes A, B, C and L, modified where specified, the compounds listed in Table 4 were prepared.

EXAMPLES 153-165

General Process D

Preparation of 4-Amino-pyrazol-3-ylcarboxylic Acid 4-Hydroxy-cyclohexylamide

Step D (i):

A mixture of 4-nitro-3-pyrazolecarboxylic acid (4.98 g, 31.7 mmol), tetrais-4-aminocyclohexanol (3.65 g, 31.7 mmol)), EDAC (6.68 34.8 mmol)) and HOBt (4.7 g, 34.8 mmol) in DMF (120 mL) was stirred at room temperature for 16 hours. The mixture was reduced in vacuo, the residue taken up in CH 2 Cl 2 and washed successively with 5% citric acid, saturated aqueous sodium bicarbonate, water and saturated aqueous sodium chloride solution. It was determined that the product was mainly in the citric acid wash, which was basified and extracted with AcOEt. The organic layer was dried over MgSO4, filtered and evaporated to give a white solid, which was triturated with CHCl3 to give 1.95 g of 4-nitro-1H-pyrazole-3-carboxylic acid 4-hydroxy-cyclohexylamide . (LC / MS: Rt 1.62, [M + H] + 255).

Step D (ii):

Introduction of the Tetrahydro-pyran-2-yl protecting group

A solution of 4-hydroxy-cyclohexylamide of 4-nitro-1H-pyrazole-3-carboxylic acid (1.95 g, 7.67 mmol) in a mixture of THF (50 mL) and chloroform (100 mL) was treated with 3,4-dihydro-2H-pyran (1.54 mL, 15.34 mmol) and p-toluenesulfonic acid monohydrate (100 mg). The reaction mixture was stirred at room temperature overnight, and then excess pyran (0.9 mL) was added from the total to bring reaction to completion. The reaction mixture was diluted with CH 2 Cl 2 and washed successively with saturated aqueous sodium bicarbonate, water and brine. The resulting solution was reduced in vacuo and subjected to Biotage column chromatography, eluting with hexane (2 column lengths) followed by 30% ethyl acetate: hexane (10 column length), 70% ethyl acetate: hexane ( 10 column length) to give 1.25 g of 4-nitro-1- (tetrahydro-pyran-2-carboxylic acid [4- (tetrahydro-pyran-2-yloxy) -cyclohexyl] yl) -1H-pyrazole-3-carboxylic acid (LC / MS:

Rt 2.97, [M + H] +423).

Step D (iii):

A solution of 4-nitro-1- (tetrahydro-pyran-2-yl) -1H-pyrazole-3-carboxylic acid [4- (tetrahydro-pyran-2-yloxy) -cyclohexyl] (0.3 g, 0.71 mmol) in methanol (25 mL) was treated

with 10% palladium on charcoal (30 mg), then hydrogenated at room temperature and pressure overnight. The catalyst was removed by filtration and washed three times with methanol. The filtrate was evaporated to give 0.264 g of the required product. (LC / MS: Rt 2.39, [M + H] + 393).

General Process E

Removal of a Tetrahydropyran-2-yl Protecting Group To a suspension of 4- (2-methoxy-benzoylamino) -6- [4- (tetrahydro-pyran-2-yloxy) -cyclohexyl] Yl) -1H-pyrazole-3-carboxylic acid (0.125 g, 0.23 mmol) in EtOH (10 mL) was added p-toluenesulfonic acid hydrate (90 mg, The reaction was diluted with EtOAc and washed successively with saturated aqueous sodium bicarbonate, water and brine The resulting solution was reduced in vacuo to give a white solid which contained traces of p-toluenesulfonic acid hydrate The solid was then taken up in EtOAc and washed with 1 M NaOH and then with saturated aqueous sodium chloride solution. and then triturated with ether / hexane to give 10 mg of the required product. (LC / MS: Rt 2.29, [M + H] + 359)

General Procedure F

Preparation of a Urea from a 4-Amino-pyrazole-3-carboxylic Acid Amide To a solution of 4-amino [4- (tetrahydro-pyran-2-yloxy) -cyclohexyl] 2-yl-1H-pyrazole-3-carboxylic acid (80 mg, 0.2 mmol) in toluene (2 mL) was added phenylisocyanate (929 mg, 0.24 mmol). The reaction was diluted with AcOEt and washed successively with water and saturated aqueous sodium chloride solution The resulting solution was reduced in vacuo to give yellow oil This was used without further purification (LC / MS: Rt 2.28, [M + H] + 344).

General Process G

Conversion of a 4-Amino-pyrazole group to a 4- (Morpholine-4-carbonylamino) -pyrazole group To a solution of 4-amino-pyrazole [4- (tetrahydro-pyran-2-yloxy) -cyclohexyl] 2-yl-1H-pyrazole-3-carboxylic acid (0.1 g, 0.255 mmol) in CH2 Cl2 (5 mL) at -10 Â ° C was added dropwise , a solution of 20% phosgene in toluene The reaction mixture was stirred at -10 ° C for 15 min and then morpholine

(0.765 mmol). The reaction mixture was allowed to warm to room temperature over 1 hour, then stirred at room temperature overnight. The reaction was diluted with CH 2 Cl 2 and washed successively with saturated sodium bicarbonate and brine. The resulting solution was reduced in vacuo to give a yellow oil which was used without further purification. (LC / MS: Rt 1.68, [M + H] + 338).

General Procedure H

Preparation of N-Oxides To a suspension of the compound of Example 53 (7.7 mg, 0.02 mmol) in CH2 Cl2 (0.5 mL) was added meta-chloroperbenzoic acid (MCPBA) (3.6 mg, 0.02 mmol). The reaction mixture was stirred at room temperature overnight and then evaporated. The residue was purified by preparative LC / MS, to give 3 mg of the required product. (LC / MS: Rt 1.83, [M + H] + 380)

General Procedure I

Removal of a benzyloxycarbonyl protecting group

A solution of the compound of Example 130 (0.2 g, 0.39 mmol) in AcOEt (40 mL) was treated with 10% palladium on charcoal (20 mg), then hydrogenated at ambient temperature and pressure for 3 hours. The catalyst was removed by filtration and washed three times with AcOEt. The filtrate was evaporated and the residue was chromatographed using 10% MeOH-CH2 Cl2 then 20% MeOH-CH2 Cl2 to give 80 mg of the required product. (LC / MS: Rt 1.88, [M + H] + 378).

General Procedure J

Mesylation of an Amine To a solution of the compound of Example 163 (20 mg, 0.05 mmol) in CH 3 CN (3 mL) was added methanesulfonyl chloride (0.0045 mL, 0.058 mmol) followed by Hunig's base (0.018 mL, 0.1 mmol). The reaction mixture was stirred at room temperature for 2 hours and then evaporated. The residue was purified by preparative LC / MS to give 8 mg of the required product. (LC / MS: Rt 2.54, [M + H] + 456).

Following Processes A to L the compounds set forth in Table 5 were prepared.

General Process M

Formation of the pyrazole 4-amide group

To a stirred solution of 4-amino-1-Boc-piperidine (10.2 mg, 51 mmol), 4-nitropyrazole-3-carboxylic acid (7.3 g, 15.9 mmol) (10.7 g, 55.8 mmol) and HOAt (55.8 g, 19.1 mmol) in DMF (100 mL), and then stirred at room temperature overnight. The solvent was removed by evaporation under reduced pressure and the residue triturated with water (250 mL). The resulting solid cream was collected by filtration, washed with water, then dried under vacuum to give 13.05 g of 4 - [(4-nitro-1H-pyrazole-3-carbonyl) -amino] ] -piperidine-1-carboxylic acid (LC / MS: Rt 2.50, [M + H] + 340). 4 - [(4-Nitro-1H-pyrazole-3-carbonyl) -amino] -piperidine-1-carboxylic acid tert-butyl ester (13.05 g) was dissolved in ethanol / DMF (300 mL / 75 mL) , treated with 10% palladium on charcoal (500 mg), then hydrogenated at room temperature and pressure overnight. The catalyst was removed by filtration through Celite and the filtrate evaporated and reevaporated with toluene. The crude material was purified by flash column chromatography eluting with AcOEt, then 2% MeOH / EtOAc after 5% MeOH / AcOEt. The product-containing fractions were combined and evaporated to give 8.78 g of 4 - [(4-amino-1H-pyrazole-3-carbonyl) -amino] -piperidine-1-carboxylic acid tert-butyl ester as a brown foam . (LC / MS: Rt 1.91, [M + H] + 310). To a stirred solution of 4 - [(4-amino-1H-pyrazole-3-carbonyl) -amino] -piperidine-1-carboxylic acid tert-butyl ester (200 mg, 0.65 mmol), EDAC (150 mg, 0.78 mmol) and HOBt (105 mg, 0.78 mmol) in 5 mL of N, N-dimethylformamide was added the corresponding carboxylic acid (0.25 mmol) and the mixture was then left at room temperature overnight. The reaction mixture was diluted with saturated aqueous sodium bicarbonate solution and the product collected by filtration and dried under vacuum. The Boc protected compound was dissolved in saturated HCl / EtOAc and stirred at room temperature for 3 hours. The product was collected by filtration, washed with diethyl ether and dried under vacuum.

General Procedure N

Preparation of 1-tert-Butyl-piperidin-4-ylamine

To a solution of 1-ethyl-4-oxopiperidine (25 g, 0.197 mol) in acetone (250 mL) at RT in a water bath was added methyl iodide (15.5 mL, 0.25 mol ) at such a rate to maintain the temperature below 30øC. The mixture was filtered and the precipitate washed with acetone and dried to afford 1-ethyl-1-methyl-4-oxopiperidinium iodide (45 g) (LC / MS: Rt 0.38, [M + H] + 143).

To a solution of t-butylamine (78.2 mL, 0.74 mol) in toluene (400 mL) was added a solution of 1-ethyl-1-methyl-4-oxopiperidinium iodide (40 g , 0.148 mol) and sodium bicarbonate (1.245 g, 0.014 mol) in water (60 mL). The reaction mixture was heated at 78 ° C for 6 hours and then allowed to cool to room temperature. The layers were separated and the aqueous layer was washed with EtOAc. The organics were combined and washed with brine, dried (MgSO4), filtered and reduced in vacuo to give 1-tert-butyl-4-oxopiperidine (14g) (LC / MS: Rt 0.39, M + H] + 156).

Step N (iii)

A solution of 1-tert-butyl-4-oxopiperidine (3.6 g, 23.1), benzylamine (5.1 mL, 46.8 mmol), acetic acid (1.5 mL) and sodium triacetoxyborohydride (7.38 g, 34.8 mmol) was stirred at ambient temperature for 2 days. The reaction mixture was reduced in vacuo, the residue partitioned between aqueous K 2 CO 3 and AcOEt. The organic portion was dried (Na2 SO4 > 4), filtered and reduced in vacuo. The residue was subjected to chromatography using CH 2 Cl 2 / MeOH / NH 4 OH (87/12/1) as the eluent to give N-benzyl-1-tert-butylpiperidin-4-amine (1.5 g) (LC / MS: 45, [M + H] + 247).

Step N (iv)

A solution of N-benzyl-1-tert-butylpiperidin-4-amine (1.56 g) and 10% palladium on charcoal (2 g) in MeOH (250 mL) was hydrogenated on a Parr shaker at 50 psi for 16 hours. hours. The solution was filtered and the reaction mixture reduced in vacuo to give 1-tert-butylpiperidin-4-amine (0.64 g) (LC / MS: Rt 02.31, without [M + H] +). EXAMPLE 165 Synthesis of 4- (2,6-Difluoro-benzoylamino) -1H-pyrazole-3-carboxylic acid [5-fluoro-2- (1-methyl-piperidin-4-yloxy) -phenyl] . Synthesis of 4-nitro-1H-pyrazole-3-carboxylic acid methyl ester

Thionyl chloride (2.90 mL, 39.8 mmol) was slowly added to a mixture of 4-nitro-3-pyrazolecarboxylic acid (5.68 g, 36.2 mmol) in EtOH (100 mL) at ambient temperature and the mixture stirred for 48 h. The mixture was reduced in vacuo and dried through an azeotrope with toluene to provide 4-nitro-1H-pyrazole-3-carboxylic acid ethyl ester as a white solid (6.42 g, 96%). (400 MHz, DMSO-d 6) δ 14.4 (s, 1H), 9.0 (s, 1H), 4.4 (q, 2H), 1.3 (t, 3H)). 165B. Synthesis of 4-amino-1 H -pyrazole-3-carboxylic acid ethyl ester

A mixture of 4-nitro-1H-pyrazole-3-carboxylic acid ethyl ester (6.40 g, 34.6 mmol) and 10% Pd / C (650 mg) in EtOH (150 mL) was stirred under atmosphere for 20 h. The mixture was filtered through a plug of Celite, reduced in vacuo and dried through an azeotrope with toluene to provide 4-amino-1H-pyrazole-3-carboxylic acid ethyl ester as a pink solid (5.28 g, 98%). (400 MHz, DMSO-d 6) δ 12.7 (s, 1), 7.1 (s, 1 Η), 4.8 (s, 2H), 4.3 (q, 2H), 1.3 (t, 3H)). 165C. Synthesis of 4- (2,6-Difluoro-benzoylamino) -β-pyrazole-3-carboxylic acid ethyl ester

A mixture of 2,6-difluorobenzoic acid (6.32 g, 40.0 mmol), 4-amino-1H-pyrazole-3-carboxylic acid ethyl ester (5.96 g, 38.4 mmol), EDC ( 8.83 g, 46.1 mmol) and HOBt (6.23 g, 46.1 mmol) in DMF (100 mL) was stirred at room temperature for 6 h. The mixture was reduced in vacuo, water was added and the formed solid collected by filtration and air dried to give 4- (2,6-difluoro-benzoylamino) -1H-pyrazole-3-carboxylic acid ethyl ester as the major component of a mixture (15.3 g). (LC / MS: Rt 3.11, [M + H] + 295.99). 165D. Synthesis of 4-2,6-difluoro-benzoylamino) -1H-pyrazole-3-carboxylic acid

A mixture of 4- (2,6-difluorobenzoylamino) -1H-pyrazole-3-carboxylic acid ethyl ester (10.2 g) in 2M aqueous NaOH / MeOH (1: 1, 250 mL) was stirred at at room temperature for 14 h. The volatiles were removed in vacuo, water (300 mL) added and the mixture stirred at pH 5 using 1 aqu aqueous HCl. The resulting precipitate was collected by filtration and dried through an azeotrope with toluene to provide 4- (2,6-difluoro-benzoylamino) -1H-pyrazole-3-carboxylic acid as a pink solid (5.70 g) . (LC / MS: Rt 2.33, [M + H] + 267.96). 165E. Synthesis of 5-fluoro-2- (1-methyl-piperidin-4-yloxy) -phenylamine

3,4-Dinitrofluorobenzene (1.86 g, 10 mmol) and 4-hydroxy-1-methylpiperidine (1.38 g, 12 mmol) in THF (20 mL) were dissolved and stirred at room temperature, while sodium (60% dispersion in mineral oil, 0.40 g, 10 mmol) in several sticky portions. The reaction mixture was stirred for one hour and then reduced in vacuo, partitioned between ethyl acetate and water, and the organic phase washed with brine, dried (MgSO4), and reduced in vacuo. The resulting residue was subjected to column chromatography, eluting with 5% MeOH / DCM to give a yellow solid (1.76 g, 2: 1 ratio of 4- (3,4-dinitro-phenoxy) -1-methyl- piperidine and a 4- (4-fluoro-2-nitro-phenoxy) -1-methyl-piperidine).

A sample of the product mixture obtained (0.562 g) was dissolved in DMF (10 mL) under a nitrogen atmosphere. Palladium on charcoal (10%, 0.056 g) was added and the reaction mixture was stirred under an atmosphere of hydrogen for 40 hours. The solids were removed by filtration and the filtrate reduced in vacuo, taken up in ethyl acetate, washed (aqueous saturated ammonium chloride solution, then brine), dried (MgSO4) and reduced in vacuo to give 5-fluoro-2- (1-methyl-piperidin-4-yloxy) -phenylamine) as a brown oil (0.049 g, 7%). (400 MHz, MeOD-di) δ 6.6 (m, 2H), 6.4 (m, 1H), 4.3 (m, 1H), 2.7 (m, 2H), 2. , 3 (m, 2H), 1.9 (m, 2H), 1.7 (m, 2H)). 165F. Synthesis of 4- (2,6-Difluoro-benzoylamino-1H-pyrazole-3-carboxylic acid [5-fluoro-2- (1-methyl-piperidin-4-yloxy) -phenyl]

5-Fluoro-2- (1-methyl-piperidin-4-yloxy) -phenylamine) (0.049 g, 0.22 mmol) was combined with 4- (2,6-difluoro-benzoylamino) -1H-pyrazole-3- (0.053 g, 0.20 mmol), EDC (0.048 g, 0.25 mmol), HOBt (0.034 g, 0.25 mmol) and DMF (1 mL) and the resulting reaction mixture was stirred at room temperature for 18 hours . The reaction mixture was reduced in vacuo and purified by preparative LC / MS to give 4- (2,6-Difluoro-phenyl) -pyrazolo [1,5-a] benzoylamino) -1H-pyrazole-3-carboxylic acid as a chamois solid. (0.010 g, 11%) (LC / MS: Rt 2.19, [M + H] + 474.27). EXAMPLE 166 Synthesis of 4- (2,6-Difluoro-benzoylamino) -1H-pyrazole-3-carboxylic acid [5-fluoro-2- (2-pyrrolidin-1-yl-ethoxy) -phenyl]

3,4-Dinitrofluorobenzene (0.93 g, 5 mmol) and 1- (2-hydroxyethylpyrrolidine) (0.69 g, 6 mmol) were dissolved in THF (10 mL) and stirred at room temperature while sodium (60% dispersion in mineral oil, 0.24 g, 6 mmol) in several small portions. The reaction mixture was stirred for 5 hours, diluted with ethyl acetate and the combined organics washed with water and brine, dried (MgSO4) and reduced in vacuo. The resulting residue was subjected to column chromatography, eluting with 5% MeOH / DCM to give an orange oil (0.94 g, 1: 1 ratio of 1- [2- (3,4-dinitro-phenoxy) -ethyl ] -pyrrolidine and 1- [2- (4-Fluoro-2-nitro-phenoxy) -ethyl] -pyrrolidine.

A sample of the product mixture obtained (0.281 g) was dissolved in DMF (5 mL) under a nitrogen atmosphere. Palladium on charcoal (10%, 0.028 g) was added and the reaction mixture was stirred under an atmosphere of hydrogen for 20 hours. The solids were removed by filtration and the filtrate reduced in vacuo and combined with 4- (2,6-difluorobenzoylamino) -1H-pyrazole-3-carboxylic acid (0.134 g, 0.50 mmol),

EDC (0.116 g, 0.60 mmol), HOBt (0.081 g, 0.60 mmol) and DMF (2.5 mL) and the resulting reaction mixture was stirred at room temperature for 18 hours. The reaction mixture was reduced in vacuo and the residue partitioned between ethyl acetate (50 mL) and saturated aqueous sodium bicarbonate solution (50 mL). The organic layer was washed with brine, dried (MgSO4) and reduced in vacuo to give the intermediate amides. Acetic acid (10 mL) was added to the crude amide and the mixture was heated to reflux for 3 hours and then reduced in vacuo. 4- (2,6-Difluoro-benzoylamino) -1H-pyrazole-3-carboxylic acid [5-fluoro-2- (2-pyrrolidin-1-yl-ethoxy) -phenyl] -amide was isolated from the residue by LC Preparative MS as an off-white solid (0.040 g, 5.6%). (LC / MS: Rt 2.38, [M + H] + 474.33). EXAMPLES 167 - 223

Following the procedures described above the compounds listed in Table 6 were prepared.

EXAMPLE 224 4- (4-Methyl-piperazin-1-yl) -1H-pyrazole-3-carboxylic acid (4-fluoro-phenyl)

Bis (2-chloroethyl) methylamine hydrochloride (97 mg, 0.5 mmol) was added to a stirred solution of 4-amino-1 H -pyrazole-3-carboxylic acid (4-fluorophenyl) (20 mg, 0.045 mmol) and diisopropylethylamine (200 μL) 1.13 mmol) in DMF (5 mL), and the resulting mixture was heated to 200 ° C (100 W) for 30 minutes on a CEM Discover ™ microwave synthesizer. The DMF was removed in vacuo, then purified by flash column chromatography, eluting with dichloromethane / methanol / acetic acid / water (90: 18: 3: 2). The product-containing fractions were combined and evaporated, treated with HCl in ethyl acetate and then reevaporated with toluene (2 x 20 mL) to give an off-white solid (27 mg). (LC / MS: Rt 1.64, [M + H] + 378). EXAMPLE 225 (4-Fluoro-phenyl) -amide of 4-morpholin-4-yl-1H-pyrazole-3-carboxylic acid

The compound was prepared in a manner analogous to Example 224, but using bis (2-chloroethyl) ether instead of bis (2-chloroethyl) methylamine hydrochloride. (LC / MS: rt 2.48 [M + H] + 291). EXAMPLE 226 4- (2,4-Dichloro-phenyl) -1H-pyrazole-3-carboxylic acid 4- (4-methylpiperazin-1-yl) benzylamide

226A. Preparation of 4- (2,4-dichloro-phenyl) -1H-pyrazole-3-carboxylic acid

A solution of 4- (2,4-dichloro-phenyl) -1H-pyrazole-3-carboxylic acid ethyl ester (205 mg, 0.72 mmol) and lithium hydroxide monohydrate (125 mg, 2.9 mmol) in THF / water 1: 1 (10 mL) was heated at 60 ° C overnight. The THF was removed by evaporation, the aqueous phase acidified with 1 M hydrochloric acid, then extracted with ethyl acetate (20 mL). The ethyl acetate layer was dried (MgSO 4), filtered and evaporated to give 200 mg of 4- (2,4-dichloro-phenyl) -1H-pyrazole-3-carboxylic acid. (LC / MS: [M + H] + 256.85). 226B. Preparation of 4- (2,4-dichloro-phenyl) -1H-pyrazole-3-carboxylic acid 4- (4-methyl-piperazin-1-yl) -benzylamide

A solution of 4- (2,4-dichloro-phenyl) -1H-pyrazole-3-carboxylic acid (70 mg, 0.27 mmol), 4- (4-methyl-piperazin-1-yl) -benzylamine EDAC (63 mg, 0.33 mmol) and HOBt (45 mg, 0.33 mmol) in 5 mL of DMF was stirred at room temperature for 48 hours. The reaction was evaporated and the residue partitioned between ethyl acetate and saturated aqueous sodium chloride solution. The ethyl acetate layer was separated, dried (MgSO4), filtered, evaporated then dried again under vacuum to give 4- (4-methyl-piperazin-1-yl) -benzylamide , 4-dichloro-phenyl) -1H-pyrazole-3-carboxylic acid. (LC / MS: Rt 2.42 [M + H] + 444). EXAMPLE 22 4- (2,4-Dichloro-phenyl) -1H-pyrazole-3-carboxylic acid 4-methylsulfamoylmethyl benzylamide

The title compound was prepared in a manner analogous to Example 226, but using (4-aminomethyl-phenyl) -N-methyl-methanesulfonamide as the starting material. 6 mg of product was isolated as a white solid. (LC / MS: Rt: 3.56 [M + H] +440). EXAMPLE 228 *

4-Phenyl-1H-pyrazole-3-carboxylic acid amide

228A. To a solution of benzaldehyde (2 g, 18.9 mmol) and malononitrile (1.37 g, 20.7 mmol) in ethanol (40 mL) was added 5 drops of piperidine and 2-benzylidene-but-3-ynitrile the mixture was heated to reflux overnight. The reaction was cooled, evaporated, then purified by flash column chromatography eluting with 1: 9 ethyl acetate / hexane and the fractions containing product combined and evaporated to give 930 mg of 2-benzylidene-but-3-ynitrile. 228B. 4-phenyl-5-trimethylsilanyl-1H-pyrazole-3-carbonitrile

N-Butyllithium (2.7 M solution in heptane) (3.3 mL, 9 mmol) was added dropwise to a stirred solution of trimethylsilyldiazomethane (2 M solution in diethyl ether) (4 , 5 mL, 9 mmol) in anhydrous THF (10 mL) at -78 ° C under a nitrogen atmosphere, then stirred for another 30 minutes. To this was added dropwise a solution of 2-benzylidene-but-3-ynitrile (920 mg, 6 mmol) in anhydrous THF (5 mL), the mixture stirred for 30 minutes at -78 ° C, then allowed to gradually cool to room temperature overnight. The reaction mixture was diluted with ethyl acetate (30 mL) then washed with saturated ammonium chloride solution followed by brine. The ethyl acetate layer was separated, dried (MgSO4), filtered and evaporated. The crude product was purified by flash column chromatography eluting with 1: 8 ethyl acetate / hexane then 1: 4 and the fractions containing product combined and evaporated to give 1.0 g of 4-phenyl-5-trimethylsilanyl-1H -pyrazole-3-carbonitrile. 228C. 4-phenyl-1H-pyrazole-3-carboxylic acid 4-Phenyl-5-trimethylsilanyl-1H-pyrazole-3-carbonitrile (500 mg, 2.1 mmol) was dissolved in 1 ml of ethanol, treated with potassium (600 mg) in water (3 mL) was then heated at 150øC (100 W) for 30 minutes then 170øC (100 W) for 20 minutes on a CEM Discover ™ microwave synthesizer. The reaction mixture was acidified to pH1 with concentrated hydrochloric acid, diluted with water (40 mL) then extracted with ethyl acetate (2 x 40 mL). The combined ethyl acetate layers were separated, dried (MgSO4), filtered and evaporated to give a 3: 1 mixture of 4-phenyl-1H-pyrazole-3-carboxylic acid and 4-phenyl-1H-pyrazole- 3-carboxylic acid. A 50 mg batch of the crude material was purified by flash column chromatography eluting with 5% methanol / dichloromethane, and the fractions containing product combined and evaporated to give 15 mg of 4-phenyl-1H-pyrazole-3 carboxylic acid as a white solid. (LC / MS: Rt 2.15 [M + H] + 188). EXAMPLE 229 4-Phenyl-1H-pyrazole-3-carboxylic acid phenylamide

A solution of 4-phenyl-1H-pyrazole-3-carboxylic acid (75 mg, 0.4 mmol) (prepared according to Example 228C), aniline (45 μL, 0.48 mmol), EDAC (92 mg, 0.48 mmol) and HOBt (65 mg, 0.48 mmol) in 5 mL of DMF was stirred at room temperature overnight. The reaction was evaporated, then purified by flash column chromatography eluting with 1: 3 ethyl acetate / hexane then 1: 2. The product-containing fractions were combined and evaporated to give 30 mg of 4-phenyl-1H-pyrazole-3-carboxylic acid phenylamide as a white solid. (LC / MS: Rt 3.12 [M + H] + 264). EXAMPLE 230 4-Phenyl-1H-pyrazole-3-carboxylic acid 4- (4-methylpiperazin-1-yl) benzylamide

The compound was prepared in a manner analogous to Example 229, but using 4- (4-methyl-piperazin-1-yl) -benzylamine as the starting material. 6 mg of product was isolated as a white solid. (LC / MS: Rt 2.05 [M + H] + 376). EXAMPLE 231 4-Phenyl-1H-pyrazole-3-carboxylic acid (6-methoxy-pyridin-3-yl)

The compound was prepared in a manner analogous to Example 230, but using 3-amino-6-methoxypyridine as an amine fragment. 100 mg of product were isolated as a pale brown solid. (LC / MS: Rt 3.17 [M + H] + 295). EXAMPLE 232 4- (3-Benzyloxy-phenyl) -1H-pyrazole-3-carboxylic acid 4- (4-methyl-piperazin-1-yl) -benzylamide

The compound was prepared in a manner analogous to Example 226. The product was isolated as a white solid. (LC / MS: Rt 2.65 [M + H] + 482). EXAMPLE 233 4- (3-Hydroxy-phenyl) -1H-pyrazole-3-carboxylic acid 4- (4-methylpiperazin-1-yl) benzylamide

A solution of 4- (3-benzyloxy-phenyl) -1H-pyrazole-3-carboxylic acid 4- (4-methyl-piperazin-1-yl) benzylamide (25 mg, 0.05 mmol) in methanol (5 mL), was treated with 10% palladium on charcoal (10 mg), then hydrogenated at room temperature and pressure overnight. The catalyst was removed by filtration through Celite and the filtrate evaporated. Purification by preparative LC / MS gave 8 mg of the required product as a cream solid. (LC / MS: Rt 1.67 [M + H] + 392). EXAMPLE 234 4- (5-Methyl-3H-imidazol-4-yl) -1H-pyrazole-3-carboxylic acid (4-fluoro-phenyl)

The compound was prepared in a manner analogous to Example 226, but using 4-methyl-5-formylimidazole as the starting material in the condensation step. The product (6 mg) was isolated as a white solid. (LC / MS: Rt 2.00 [M + H] + 286). EXAMPLE 235 4- (2,5-Dimethyl-pyrrol-1-yl) -1H-pyrazole-3-carboxylic acid (4-fluoro-phenyl)

A mixture of 4-amino-1H-pyrazole-3-carboxylic acid (4-fluoro-phenyl) -amide (100 mg) and Montemorilonite KSF clay (100 mg) in acetonylacetone (1 mL) was heated at 120 ° C (50 W) for 15 minutes on a CEM discover microwave synthesizer. The reaction mixture was diluted with 5% methanol / dichloromethane, filtered and evaporated. The crude product was purified by flash column chromatography eluting with 1: 2 ethyl acetate / hexane and the product-containing fractions were combined and evaporated to give 65 mg of the target molecule as a pale brown solid. (LC / MS: Rt 3.75 [M + H] + 299). EXAMPLE 236 *

4- (3-Hydroxymethyl-phenyl) -1H-pyrazole-3-carboxylic acid phenylamide

236A. 4-iodo-1H-pyrazole-3-carboxylic acid phenylamide

An aqueous solution of sodium nitrite (760 mg) in 2 mL of water was added dropwise to a stirred suspension of 4-amino-1H-pyrazole-3-carboxylic acid phenylamide (2 g; 10 mmol) in concentrated hydrochloric acid (20 mL) at 0 ° C, then stirred at 0 ° C for an additional 60 minutes. The reaction mixture was diluted with acetone (10 mL), then treated with potassium iodide (1.8 g) and copper (II) iodide (2.1 g) and stirred at room temperature for 90 minutes. The reaction mixture was diluted with saturated aqueous sodium chloride and ethyl acetate, then washed with saturated sodium thiosulfate solution. The ethyl acetate layer was separated, dried (MgSO 4), filtered and evaporated to give 680 mg of 4-iodo-1H-pyrazole-3-carboxylic acid phenylamide. 236B. 4-iodo-1- (4-methoxy-benzyl) -1H-pyrazole-3-carboxylic acid phenylamide

A solution of 4-iodo-1H-pyrazole-3-carboxylic acid phenylamide (670 mg, 2.14 mmol) in acetonitrile (10 mL) was treated with potassium carbonate (360 mg, 2.57 mmol)) followed by 4-methoxybenzyl chloride (320 μL, 2.35 mmol). The mixture was stirred at room temperature overnight, then evaporated under reduced pressure. The residue was partitioned between ethyl acetate and saturated aqueous sodium chloride solution; the ethyl acetate layer was separated, dried (MgSO4), filtered and evaporated. The crude material was purified by flash column chromatography eluting with 1: 3 ethyl acetate / hexane and the fractions containing product combined and evaporated to give 660 mg of 4-iodo-1- (4-methoxybenzyl) -1H-pyrazole-3-carboxylic acid. 236C. 4- (3-hydroxymethyl-phenyl) -4-methoxy-benzyl) -1H-pyrazole-3-carboxylic acid phenylamide

To a mixture of 4-iodo-1- (4-methoxybenzyl) -1H-pyrazole-3-carboxylic acid phenylamide (50 mg, 0.11 mmol), bis (tri- tert -butylphosphine) palladium (12 mg) , potassium carbonate (100 mg, 0.66 mmol) and 3- (hydroxymethyl) benzeneboronic acid (21 mg, 0.14 mmol) in ethanol / toluene / water (4 mL: 1 mL: 1 mL) was heated to 120 ° C (50 W) for 15 minutes on a CEM Discover microwave synthesizer. The reaction was evaporated and the residue partitioned between ethyl acetate and saturated aqueous sodium chloride solution. The ethyl acetate layer was separated, dried (MgSO4), filtered and evaporated and the crude material purified by flash column chromatography eluting with 1: 2 ethyl acetate / hexane then 2: 1. The product-containing fractions were combined and evaporated to give 60 mg of 4- (3-hydroxymethyl-phenyl) -1- (4-methoxy-benzyl) -1H-pyrazole-3-carboxylic acid phenylamide. 236D. 4- (3-Hydroxymethyl-phenyl) -1H-pyrazole-3-carboxylic acid phenylamide

A mixture of 4- (3-hydroxymethyl-phenyl) -1- (4-methoxy-benzyl) -1H-pyrazole-3-carboxylic acid phenylamide (20 mg) and anisole (20 μL) in trifluoroacetic acid (1 mL) was heated at 120 ° C (50 W) for 15 minutes on a CEM Discover microwave synthesizer. The reaction was evaporated, then purified by flash column chromatography eluting with 2: 1 ethyl acetate / hexane. The product-containing fractions were combined and evaporated to give 5 mg of product. (LC / MS: Rt 2.55 [M + H] + 294). EXAMPLE 237

Preparation of 4- (2,6-Dichloro-benzoylamino) -1H-pyrazole-3-carboxylic acid piperidine-4-ylamide 237A._4- (2,6-dichloro-benzoylamino) -1H-pyrazole-3- carboxylic acid

2,6-Dichlorobenzoyl chloride (8.2 g, 39.05 mmol) was added cautiously to a solution of 4-amino-1H-pyrazole-3-carboxylic acid methyl ester (prepared analogously to 165B) ( 5 g, 35.5 mmol) and triethylamine (5.95 mL, 42.6 mmol) in dioxane (50 mL) then stirred at room temperature for 5 hours. The reaction mixture was filtered and the filtrate treated with methanol (50 mL) and 2M sodium hydroxide solution (100 mL), heated at 50 ° C for 4 hours and then evaporated. 100 ml of water was added to the residue, then acidified with concentrated hydrochloric acid. The solid was collected by filtration, washed with water (100 mL) and sucked dry to give 10.05 g of 4- (2,6-dichloro-benzoylamino) -1H-pyrazole-3-carboxylic acid as a pale violet solid . 237B. 4 - {[4- (2,6-Dichloro-benzoylamino) -1H-pyrazole-3-carbonyl] -amino} -piperidine-1-carboxylic acid tert-butyl ester

A mixture of 4- (2,6-dichloro-benzoylamino) -1H-pyrazole-3-carboxylic acid (6.5 g, 21.6 mmol), 4-amino-1-BOC-piperidine (4.76 g, 23.8 mmol), EDC (5.0 g, 25.9 mmol) and HOBt (3.5 g, 25.9 mmol) in DMF (75 mL) was stirred at room temperature for 20 hours. The reaction mixture was reduced in vacuo and the residue partitioned between ethyl acetate (100 mL) and saturated aqueous sodium bicarbonate solution (100 mL). The organic layer was washed with brine, dried (MgSO4) and reduced in vacuo. The residue was taken up in 5% MeOH-DCM (~ 30 mL). The insoluble material was collected by filtration, washed with DCM and dried in vacuo to give 4 - {[4- (2,6-dichloro-benzoylamino) -1H-pyrazole-3-carbonyl] -amino acid tert-butyl ester ) -piperidine-1-carboxylic acid (5.38 g) as a white solid. The filtrate was reduced in vacuo and the residue purified by column chromatography using gradient elution of AcOEt / hexane 1: 2 until

AcOEt to give 4 - {[4- (2,6-dichloro-benzoylamino) -1H-pyrazole-3-carbonyl] -amino} -piperidine-1-carboxylic acid tert-butyl ester (2.54 g) as a white solid. 4 - (2,6-dichloro-benzoylamino) -1H-pyrazole-3-carboxylic acid 7-piperidin-4-

A solution of 4 - {[4- (2,6-dichloro-benzoylamino) -1H-pyrazole-3-carbonyl] -amino} -piperidine-1-carboxylic acid tert-butyl ester (7.9 g) in MeOH (50 mL) and EtOAc (50 mL) was treated with saturated HCl-AcOEt (40 mL) then stirred at r.t. overnight. The product does not crystallize due to the presence of methanol and therefore the reaction mixture was evaporated and the residue triturated with AcOEt. The resulting off-white solid was collected by filtration, washed with EtOAc and suction dried on a porous funnel to give 6.3 g of 4- (2,6-dichloro-benzoylamino) -1H-pyrazole-3-carboxylic acid piperidin-4- as the hydrochloride salt. (LC / MS: Rt 5.89, [M + H] + 382/384). EXAMPLE 238 4-Methanesulfonylamino-1 H -pyrazole-3-carboxylic acid (4-fluoro-phenyl)

A solution of 4-amino-1H-pyrazole-3-carboxylic acid (4-fluorophenyl) -amide (50 mg) (Example 2B) and methanesulfonic anhydride (45 mg) in pyridine (1 ml) was stirred at room temperature, overnight, then evaporated and purified by flash column chromatography eluting with 2: 1 AcOEt / hexane. Evaporation of the fractions containing the product gave 20 mg of the title compound. (LC / MS: Rt 2.87; [M + H +] 299). EXAMPLES 239 to 245

The compounds of Examples 239 to 245 were prepared using the methods described above or methods very analogous thereto. EXAMPLE 239 4- (2,6-Difluoro-benzoylamino) -1H-pyrazole-3-carboxylic acid [1- (2-fluoro-ethyl) -piperidin-4-yl]

EXAMPLE 240 4- (2,6-Dichloro-benzoylamino-1 H -pyrazole-3-carboxylic acid (6-chloro-pyridin-3-yl)

EXAMPLE 241 (benzoylamino) -1H-pyrazole-3-carboxylic acid (6-Amino-pyridin-3-yl)

EXAMPLE 242 6-Methoxy-pyridin-3-yl) -amide [4- (2,6-dichloro-benzoylamino) -1H-pyrazole-3-

EXAMPLE 243

4- [3-Chloro-5- (4-methyl-piperazin-1-yl) -benzoylamino] -1H-pyrazole-3-carboxylic acid cyclohexylamide

EXAMPLE 244 [1- (2,2-Difluoroethyl) -piperidin-4-yl] -amide 4- (2,6-difluoro-benzoylamino) -1H-pyrazole-3-

EXAMPLE 245

4- [3- (4-Methyl-piperazin-1-yl) -benzoylamino] -1H-pyrazole-3-carboxylic acid cyclohexylamide

BIOLOGICAL ACTIVITY EXAMPLE 246

Measurement of CDK2 Kinase Inhibitory Activity (IC 50)

Compounds of formula (II) were tested for kinase inhibitory activity using the following protocol or the activated CDK2 / cyclin A kinase protocol described in Example 241. 1.7 ul of active CDK2 / Cyclin A (Upstate

Biotechnology, 10U / μl) in assay buffer (250 μl of 10X potentiometer assay (200 mM MOPS pH 7.2, 250 mM β-glycerophosphate, 50 mM EDTA, 150 mM MgCl2), 11.27 μl of ATP 10 mM, 2.5 pL

1 μM DTT, 25 μl 100 mM sodium orthovanadate, 708.53 μl H2 O), and 10 μl mixed with 10 μl histone substrate mixture (60 μl bovine histone HL (Upstate Biotechnology, 5 mg / ml) ), 940 μL of H2 O, 35 μCi of γ33Ρ-ΑΤΡ) and added to 96-well plates along with 5 μl of various dilutions of the test compound in DMSO (up to 2.5%). The reaction is allowed to proceed for 5 hours before quenching with an excess of orthophosphoric acid (30 æl 2%). Ο 33γ-ΑΤΡ remaining to be incorporated into histone H1 is separated from phosphorylated histone H1 on a Millipore MAPH filtration plate. The wells of the MAPH plate are moistened with 0.5% orthophosphoric acid, and then the reaction results are filtered with a Millipore vacuum filtration unit through the wells. After filtration, the residue is washed twice with 200 μl of 0.5% orthophosphoric acid. Once the filters are dried, 25 μl of Microscint 20 scintillation agent is added, and then counted in a Packard Topcount for 30 seconds. The% inhibition of CDK2 activity is calculated and plotted to determine the concentration of test compound required to inhibit 50% of the activity of CDK2 (IC 50)

By the protocol indicated above, the compounds of Examples 2C to 87, 89-92, 94, 96-101, 104-105, 165, 166, 224, 225, 227, 229, 231, 233, 234 and 236 each have IC 50 values below 20 pM or provide at least 50% inhibition of CDK2 activity at a concentration of 10 pM. The compounds of Examples 88, 93, 226, 228, 230 and 235 each have,

IC 50 values less than 750 pM EXAMPLE 247

CDK Selectivity Assays

The compounds of formula (II) are tested for kinase inhibitory activity against a number of different kinases using the general protocol described in Example 239, but modified as set forth below.

The kinases are diluted to a working stock solution of 10 x 20 mM MOPS, pH 7.0, 1 mM EDTA, 0.1% γ-mercaptoethanol, 0.01% Brij-35, 5% glycerol, 1 mg / ml BSA. One unit is equal to the incorporation of 1 nmol phosphate per minute in 0.1 mg / mL histone HI, or CDK7 substrate peptide at 30øC with a final ATP concentration of 100æM. The substrate for all CDK assays (except CDK7) is histone HI, diluted to a 10X working stock solution in 20 mM MOPS, pH 7.4 before use. The substrate for CDK7 is a specific peptide obtained from Upstate diluted to a 10X stock solution in deionized water.

Assay Procedure for CDK1 / cyclin B, CDK2 / cyclin A, CDK2 / cyclin E, CDK3 / cyclin E, CDK5 / p35, CDK6 / cyclin D3:

In a final reaction volume of 25 pL, the enzyme (5-10 mU) is incubated with 8 mM MOPS, pH 7.0, 0.2 mM EDTA, 0.1 mg / ml histone HI, 10 mM MgAcetate and [ γ-33Ρ-ΑΤΡ] (specific activity at about 500 cpm / pmol, concentration as needed). The reaction is initiated by the addition of Mg 2+ [γ-33Ρ-ΑΤΡ]. After incubation for 40 minutes at ambient temperature the reaction is stopped by the addition of 5 æl of a 3% phosphoric acid solution. 10 mL of the reaction is applied to a P30 filtration pad and washed 3 times for 5 minutes in 75 mM phosphoric acid and once in methanol before drying and counting.

In the CDK3 / cyclin E assay, the compound of Example 150 had an IC 50 of less than 20 μ.

In the CDK5 / p35 assay, the compounds of Examples 41 and 150 had an IC 50 of less than 20 μΜ.

In the CDK6 / cyclin D3 assay, the compound of Example 150 had an IC 50 of less than 20 μ.

Test procedure for CDK7 / cyclin H / MAT1

In a final reaction volume of 25æl, the enzyme (5-10μU) is incubated with 8mM MOPS, pH 7.0, 0.2mM EDTA, 500μ peptide, 10mM MgAcetate and [γ 33Ρ-ΑΤΡ] (specific activity approx 500 cpm / pmol, concentration as needed). The reaction is initiated by the addition of Mg 2+ [γ-33Ρ-ΑΤΡ]. After incubation for 40 minutes at ambient temperature the reaction is stopped by the addition of 5 æl of a 3% phosphoric acid solution. 10 mL of the reaction is applied to a P30 filtration pad and washed 3 times for 5 minutes in 75 mM phosphoric acid and once in methanol before drying and counting. EXAMPLE 248 A. Assay for Measurement of Kinase Inhibitory Activity on CDK2 / Activated Cyclin A (IC 50)

The compounds of formula (II) were tested for kinase inhibitory activity using the following protocol. CDK2 / Cyclin A activated (Brown et al., Nat. Cell Biol., 1, pp438-443, 1999; Lowe, ED, et al. Biochemistry, 41, ppl5625-156734, 2002) is diluted to 125 pM in assay buffer with 2.5X potency (50 mM MOPS, pH 7.2, 62.5 mM β-glycerophosphate, 12.5 mM EDTA, 37.5 mM MgCl 2, 112.5 mM ATP, 2.5 mM DTT, 2.5 mM sodium, 0.25 mg / ml bovine serum albumin) and 10 Âμl were mixed with 10 Âμl of the histone substrate mixture (60 Âμl of bovine histone HI (Upstate Biotechnology, 5 mg / ml), 940 μl of H2 O, 35 μCi of γ33Ρ-ΑΤΡ) and added to 96-well plates along with 5 μl of various dilutions of the test compound in DMSO (up to 2.5%). The reaction is allowed to proceed for 2 to 4 hours before quenching with an excess of orthophosphoric acid (5 æl 2%). Ο 33γ-ΑΤΡ remaining to be incorporated into histone H1 is separated from phosphorylated histone H1 on a Millipore MAPH filtration plate. The wells of the MAPH plate are moistened with 0.5% orthophosphoric acid and then the reaction results are filtered with a Millipore vacuum filtration unit through the wells. After filtration, the residue is washed twice with 200 μl of 0.5% orthophosphoric acid. Once the filters are dried, 20 μl of Microscint 20 scintillation agent is added and then counted in a Packard Topcount for 30 seconds. The% inhibition of CDK2 activity is calculated and plotted to determine the concentration of test compound required to inhibit 50% of the activity of CDK2 (ICso)

Through the above protocol, the compounds of Examples 95, 96, 99-104, 106-121, 123-125, 130-137, 139, 142-145, 147-150, 152-156, 158-160 , 162-164, 167-173, 177-179, 181-182, 184-190, 194, 196-204, 208-213 and 215 have IC 50 values of less than 20 μ. The compounds of Examples 122, 126-129, 140, 141, 146, 157 and 161 each have IC 50 values less than 750 μΜ and most have IC 50 values less than 100 μΜ. B. CDK1 / Cyclin B Assay.

The CDK1 / Cyclin B assay is identical to CDK2 / Cyclin A above except that CDK1 / Cyclin B (Upstate Discovery) is used and the enzyme is diluted to 6.25 nM. In the CDK1 assay performed as described above or by the protocol indicated in Example 240, the compounds of Examples 2C, 41, 48, 53, 64, 65, 66, 73, 76, 77, 91, 95, 102, 106, 117, 123, 125, 133, 137, 142, 150, 152, 154, 167, 186, 187, 189,190,193,199,1999,202-204,207,1921-213,215 and 218- 223 were determined to have IC 50 values below 20 μΜ and compounds of the

Examples 188 and 206 were determined to have IC 50 values less than 100 μΜ. EXAMPLE 249

Test Procedure for CDK4

Assays for CDK4 inhibitory activity were carried out by Proqinase GmbH, Freiburg, Germany using their registered 33PanQinase® Assay Assay. Assays were performed on 96-well FlashPlates ™ (PerkinElmer). In each case, the reaction cocktail (50æl final volume) is comprised of; 20 Âμl assay buffer (60 mM HEPES-NaOH final composition, pH 7.5, 3 mM MgCl2, 3 pM Na-orthovanadate, 1.2 mM DTT, 50 pg / ml PEG2000, 5 Âμl ATP solution final concentration [1 pM γ-33PJ-ATP (approx 5x105 cpm per well)), 5 μl of test compound (in 10% DMSO), 10 μl of substrate / 10 μl of enzyme solution (premixed). The final amounts of enzyme and substrate were as below.

The reaction cocktail was incubated at 30 ° C for 80 minutes. The reaction was stopped with 50 μl of 2% H 3 PO 4, the plates were aspirated and washed twice with 200 μl of 0.9% NaCl. 33P incorporation was determined with a microplate scintillation counter. The baseline values were subtracted from the data before calculating the residual activities for each well. The IC50's were calculated using Prism 3.03. The compound of Example 150 has an IC 50 of less than 5 pM in this assay. EXAMPLE 250

Antiproliferative Activity

The antiproliferative activities of the compounds of formula (II) are determined by measuring the suitability of the compounds to inhibit cell growth in a number of cell lines. Inhibition of cell growth is measured using the Alamar Blue assay (Nociari, M., Shalev, A., Benias, P., Russo, C. Journal of Immunological Methods 1998, 213, 157-167). The method relies on the ability of viable cells to reduce resazurin to its resorufin fluorescent product. For each proliferation assay, the cells are plated in 96-well plates and allowed to recover for 16 hours prior to the addition of the inhibitor compounds for a further 72 hours. At the end of the incubation period 10% (v / v) Alamar Blue is added and incubated for a further 6 hours prior to determination of the fluorescent product at 535 nM ex / 590 nM in. In the case of non-proliferating cells, the cells are maintained at confluency for 96 hours prior to the addition of the inhibitor compounds for a further 72 hours. The number of viable cells is determined by the Alamar Blue assay as above. All cell lines are obtained from ECACC (European Collection of Cell Cultures).

In the assays against the HCT 116 human colon carcinoma cell line (ECACC No. 91091005), the compounds of Examples 10, 25-27, 41, 44, 46, 48, 50, 52, 53, 60, 62, 64- 67, 69, 73-77, 79, 80, 83A, 86, 90-93, 95-98, 100-104, 106, 107, 109-121, 123-125, 131-134, 136-143, 155, 158, 159, 162-164, 166, 167, 178, 179, 185-190, 192-205, 207-215 and 218-223 have IC50 values of less than 20 μΜ and the compounds of Examples 2C, 29, 38, 39, 49, 51, 85, 89, 99, 108, 135, 160, 182, 183, 206 and 216 have IC50 values of less than 100 μΜ. EXAMPLE 251

Measurement of inhibitory activity against Glycogen Synase-Kinase-3 (GSK-3)

The activities of the compounds of formula (II) as inhibitors of GSK-3 were determined using Protocol A or Protocol B below.

Protocol AA GSK3-p (Upstate Discovery) is diluted to 7.5 nM in 25 mM MOPS, pH 7.00, 25 mg / ml BSA, 0.0025% Brij-35R ™, 1.25% glycerol, 0.5 mM EDTA, 25 mM MgCl2, 0.025% β-mercaptoethanol, 37.5 mM ATP and 10 μl are mixed with 10 μl of the substrate mixture. The substrate mixture is 12.5 pph phosphoglycogen synthase-2 peptide (Upstate Discovery) in 1 ml of water with 35 pCi of γ33Ρ-ΑΤΡ. The enzyme and the substrate are added to 96 well plates along with 5 Âμl of various dilutions of the test compound in DMSO (up to 2.5%). The reaction is allowed to proceed for 3 hours before quenching with an excess of orthophosphoric acid (5 æl 2%). The filtration process is as for the above Activated CDK2 / Cyclin A assay.

BA protocol GSK3p (human) is diluted to a working stock solution 10x in 50 mM Tris, pH 7.5, 0.1 mM EGTA, 0.1 mM sodium vanadate, 0.1% β-mercaptoethanol, 1 mg / ml BSA. One unit is equal to the incorporation of 1 nmol phosphate per minute of phosphoglycogen synthase-2 peptide per minute.

In a final reaction volume of 25 pL, GSK3β (5-10 mU) is incubated with 8 mM MOPS 7.0, 0.2 M EDTA, YRRAAVPPSPSRSRHSSPHQS (p) 20 μM EDEEE (GS2 phosphopeptide), 10 mM MgAcetate, and [γ-33Ρ-ΑΤΡ] (specific activity at about 500 cpm / pmol, concentration as needed). The reaction is initiated by the addition of Mg 2+ [γ-33Ρ-ΑΤΡ]. After incubation for 40 minutes at ambient temperature the reaction is stopped by the addition of 5 æl of a 3% phosphoric acid solution. 10æl of the reaction is applied to a P30 filter mat and washed 3 times for 5 minutes in 50mM phosphoric acid and once in methanol prior to drying and counting. From the results of the GSK3-B assays performed using one of the two protocols indicated above, the compounds of Examples 2C, 26, 48, 53, 65, 76, 77, 84, 86, 95, 102, 106, 119, 122, 123, 126, 127, 128, 129, 131, 134, 135, 138, 140, 141, 142, 143, 144, 145, 146, 147, 149, 150 and 151 each have IC50 values less than 10 μΜ.

PHARMACEUTICAL FORMULATIONS EXAMPLE 252 (i) Tablet Formulation

A tablet composition containing a compound of formula (II) is prepared by mixing 50 mg of the compound with 197 mg of lactose (BP) as the diluent, and 3 mg of magnesium stearate as a lubricant and pressing to form a tablet in known manner. (ii) Capsule Formulation

A capsule formulation is prepared by mixing 100 mg of a compound of formula (II) with 100 mg of lactose and introducing the resulting mixture into standard opaque hard gelatin capsules.

(iii) Injectable Formulation I

A parenteral composition for administration by injection may be prepared by dissolving a compound of formula (II) (e.g., in salt form) in water containing 10% propylene glycol to give an active compound concentration of 1.5% by weight. The solution is then sterilized by filtration, introduced into an ampoule and sealed.

(iv) Injectable Formulation II

A parenteral composition for injection is prepared by dissolving in water a compound of formula (II) (eg, as a salt) (2 mg / mL) and mannitol (50 mg / mL), sterilizing the solution by filtration and introducing it into vials or 1 mL sealed ampoules. (iv) Subcutaneous Injection Formulation

A composition for subcutaneous administration is prepared by mixing a compound of formula (II) with pharmaceutical grade corn oil to give a concentration of 5 mg / mL. The composition is sterilized and filled into a suitable container. EXAMPLE 253

Determination of Antifungal Activity The antifungal activity of the compounds of formula (II) is determined using the following protocol.

The compounds are tested against a panel of fungi including Candida parsilosis, Candida tropicalis, Candida albicans-ATCC 36082 and Cryptococcus neoformans. Test organisms are maintained on sloping surfaces of Dextrose Sabourahd Agar at 4 ° C. Single-chain suspensions of each organism are prepared by culturing the yeast overnight at 27øC in a rotary drum in nitrogen-based yeast (YNB) broth with amino acids (Difco, Detroit, Mich.), PH 7.0 with morpholinopropanesulfonic acid (MOPS) 0.05. The suspension is then centrifuged and washed twice with 0.85% NaCl before sonicating the washed cell suspension for 4 seconds (Branson Sonicator, model 350, Danbury, Conn.). The singlet blastospores are counted on a hemocytometer and adjusted to the desired concentration in 0.85% NaCl. The activity of the test compounds is determined using a modification of a broth microdilution technique. Test compounds are diluted in DMSO to a rate of 1.0 mg / mL, then diluted to 64 pg / mL in YNB broth, pH 7.0 with MOPS (Fluconazole is used as a control) to provide a working solution of each compound. Using a 96-well plate, wells 1 and 3 to 12 are made with YNB broth, ten-fold dilutions of the compound solution are made in wells 2 to 11 (the concentration ranges are 64 to 0.125 pg / ml). Well 1 is used as a sterility control and blank for spectrophotometric assays. Well 12 is used as a growth control. Microtiter plates are inoculated into each of wells 2 to 11 with 10 μl (final inoculum size is 104 organisms / ml). The inoculated plates are incubated for 48 hours at 35 ° C. MIC values are determined spectrophotometrically by measuring the absorbance at 420 nm (Automatic Microplate Reader, DuPont Instruments, Wilmington, Del.) After shaking the plates for 2 minutes with a vortex mixer (Vorte-Genie 2 Mixer, Scientific Industries, Inc. , Bolemia, NI). The MIC criterion is defined as the lowest concentration of drug that exhibits approximately 50% (or more) growth reduction compared to the control well. With the turbidity assay, this is defined as the lowest concentration of drug at which the turbidity in the well is <50% of the control (IC 50). The Concentrations

Minimal Citolytic (MCC) are determined by subcultured all wells of the 96-well plate in a Sabourahd Dextrose Agar (SDA) plate, incubating for 1 to 2 days at 35øC and then verifying the viability. EXAMPLE 254

Protocol for the Biological Evaluation of Food

Fungal Infection in Whole Plants in vivo

The compounds of formula (II) are dissolved in acetone, with subsequent successive dilutions in acetone to obtain a desired concentration range. Final volumes of treatment are obtained by adding 9 volumes of 0.05% aqueous Tween-20 ™ or 0.01% Triton X-100 ™ depending on the pathogen.

The compositions are then used to test the activity of the compounds of the invention against tomato mildew (Phytophthora infestans) using the following protocol. Tomatoes (Rutgers cultivar) are grown from the seed in a groundless peat pot mix until the shoots are 10-20 cm high. The plants are then sprayed to the test compound at a dilution of 100 ppm.

After 24 hours, the test plants are inoculated by spraying with an aqueous suspension of Phytoftora infestans sporangia, and kept in a dew chamber overnight. The plants are then transferred to the greenhouse until disease develops in untreated control plants.

Similar protocols are also used to test the activity of the compounds of the invention to combat Rust

Wheat (Puccinia), Wheat Oídium (Ervsiphe vraminis), Wheat (Monon), Septoria tritici (Septoria tritici) and Wheat Glume Septoriose (Leptosphaeria nodorum).

Claims (14)

The compound comprises: (i) A compound of formula (II): or salts or tautomers or N-oxides or solvates thereof; wherein Y is a bond or an alkylene chain of 1, 2 or 3 carbon atoms in length; R 1 is a carbocyclic or heterocyclic group having from 3 to 12 endocyclic members, wherein the carbocyclic or heterocyclic groups are unsubstituted or substituted with one or more substituent groups R 10; R2 is hydrogen or methyl; R 3 is selected from non-aromatic carbocyclic and heterocyclic groups having from 3 to 12 endocyclic members, wherein the carbocyclic or heterocyclic groups are unsubstituted or substituted with one or more substituent groups R 10; and R10 is selected from halogen, hydroxy, trifluoromethyl, cyano, nitro, carboxyl, amino, C1-4 mono- or dihydrocarbylamino, carbocyclic and heterocyclic groups having from 3 to 12 endocyclic members; a Ra-Rb group wherein R a is a bond, O, CO, Χ 20 (Χ 2), C (X 2) X 2, X 1 C (X 2) X 1, S, SO, SO 2, NRC, SO 2 NR c, or NR c SO 2; and Rb is selected from hydrogen, carbocyclic and heterocyclic groups having from 3 to 12 endocyclic members, and a C1-8 alkyl group optionally substituted with one or more substituents selected from hydroxy, oxo, halogen, cyano, nitro, carboxyl, amino, mono - or di-C 1-4 hydrocarbylamino, carbocyclic and heterocyclic groups having from 3 to 12 endocyclic members, R c is selected from hydrogen and C 1-4 hydrocarbyl; and X 1 is O, S or NRC and X 2 is = O, = S or = NRC; and provided that when the substituent group R 10 comprises or includes a carbocyclic or heterocyclic group, said carbocyclic or heterocyclic group may be unsubstituted or may itself be substituted with one or more substituent groups R 10 and additionally wherein (a) these other substituent groups R 10 include carbocyclic or heterocyclic groups, which are not themselves yet substituted; or (b) said other substituents do not include carbocyclic or heterocyclic groups, but are otherwise selected from the groups listed above in the definition of R 10; and (ii) one or more other therapeutic agents. A combination according to claim 1, wherein R 2 is hydrogen. A combination according to any one of the preceding claims wherein R1 is a substituted or unsubstituted monocyclic heterocyclic or carboxylic group in which the carbocyclic and heterocyclic groups are substituted by one or more substituent groups R10 or R10a; wherein R10 is as defined in claim 1 and R10a is selected from halogen, hydroxy, trifluoromethyl, cyano, nitro, carboxyl, a group Ra-Rb wherein Ra is a bond, O, CO, X3 C (X4), C (X4 ), And Rb is selected from hydrogen and a C1-8 alkyl group optionally substituted with one or more substituents selected from hydroxy, oxo, halogen, cyano, nitro, carboxyl and C1-6 alkyl; non-aromatic monocyclic carbocyclic or heterocyclic groups having from 3 to 6 ring members. A combination according to claim 1 wherein the compound of formula (II) is of formula (IV): or salts or tautomers or N-oxides or solvates thereof; wherein R1 and R2 are as defined herein; an optional second bond may be present between the carbon atoms numbered 1 and 2; one of U and T is selected from CH2, CHR13, CR11R13, NR14, N (O) R15,0 and S (O) t; and the other of U and T is selected from, NR 14, O, CH 2, CHR 11, C (R 11) 2 and C = O; r is 0, 1, 2, 3 or 4; t is 0, 1 or 2; R11 is selected from hydrogen, halogen (particularly fluoro), C1-3 alkyl (e.g., methyl) and C1-3 alkoxy (e.g., methoxy); R 13 is selected from hydrogen, NHR 14, NOH, NOR 14 and Ra-R b; R14 is selected from hydrogen and Rd-Rb; Rd is selected from a bond, CO, C (X2) X4, SO2 and SC> 2NRC; Ra, Rb and Rc are as defined above; and R 15 is selected from saturated C 1-4 hydrocarbyl optionally substituted with hydroxy, C 1-2 alkoxy, halogen or a 5- or 6-membered monocyclic carbocyclic or heterocyclic group, with the proviso that U and T can not be simultaneously. The combination according to claim 4 wherein the compound of formula (II) is of formula (Va): or salts or tautomers or N-oxides or solvates thereof; wherein R14a is selected from hydrogen, C1-4 alkyl optionally substituted with fluoro, cyclopropylmethyl, phenyl-C 1-2 alkyl, C 1-4 alkoxycarbonyl, phenyl-C 1-2 alkoxycarbonyl, C 1-2 alkoxy C1-4 alkyl and C1-4 alkylsulfonyl, wherein the phenyl moieties when present are optionally substituted with one to three substituents selected from fluoro, chloro, C1-4 alkoxy optionally substituted with fluoro or C1-2 alkoxy, and C 1-4 alkyl optionally substituted with fluoro or C 1-2 alkoxy; w is 0, 1, 2 or 3; R2 is hydrogen or methyl; R11 and r are as defined in any one of claims 17 to 19; and R 19 is selected from fluorine; chloro; C 1-4 alkoxy optionally substituted with fluoro or C 1-12 alkoxy; and C 1-4 alkyl optionally substituted with fluoro or C 1-2 alkoxy. A combination according to claim 1 wherein the compound of formula (II) is of formula (VIb): or salts or tautomers or N-oxides or solvates thereof; wherein R 20 is selected from hydrogen and methyl; R 21a is selected from fluorine and chlorine; and R 22a is selected from fluoro, chloro and methoxy. A combination according to claim 6, wherein the compound of the formula (II) is 4- (2,6-dichloro-benzoylamino) -1H-pyrazole-3-carboxylic acid piperidin-4-ylamine or a pharmaceutically acceptable salt thereof. salt. A combination according to any preceding claim, wherein one or more other therapeutic agents are selected from anticancer agents, including: - Topoisomerase inhibitors - Alkylating agents - Antimetabolites - DNA binders Microtubule inhibitors (tubulin targeting agents) - monoclonal antibodies - signal transduction inhibitors - radiation therapy A combination according to any preceding claim, wherein the one or more other therapeutic agents are selected from anticancer agents, including cisplatin, cyclophosphamide, doxorubicin, irinotecan, fludarabine, 5-FU, taxanes, and mitomycin C. A combination according to any one of the preceding claims wherein the compound of formula (II) and one or more other therapeutic agents are administered simultaneously or sequentially. A combination according to any preceding claim, wherein the compound of formula (II) and one, two, three, four or more other therapeutic agents are formulated together in a dosage form containing two, three, four or more therapies. A combination according to any one of the preceding claims for use in medicine, for example for the treatment of a cancer. A pharmaceutical composition (for example formulation) comprising at least one compound of formula (II) as defined in any one of claims 1 to 7 together with one or more pharmaceutically acceptable carriers, adjuvants, excipients, diluents, fillers, buffers, stabilizers, preservatives, lubricants, and other therapeutic or prophylactic agents. A compound of formula (II) as defined in any one of claims 1 to 7 for use in the treatment of a disease which is: - viral infections, for example herpesviruses, variola virus, Epstein-Barr virus, Sindbis virus, adenovirus, HIV, HPV, HCV and HCMV; prevention of AIDS development in HIV-infected individuals; or - type II or non-insulin-dependent diabetes mellitus; or - autoimmune diseases; or - head trauma; or - stroke; or - pileopathy; or dementia, neurodegenerative disorders, AIDS-related eg Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, retinitis pigmentosa, spinal muscular atropy and cerebellar degeneration or such as, motor neuronal Alzheimer's disease, progressive supranuclear palsy, cortical degeneration -basal and Pick disease; or - chronic inflammatory diseases, for example systemic lupus erythematosus, autoimmune mediated glomerulonephritis, rheumatoid arthritis, psoriasis, inflammatory bowel disease, and autoimmune diabetes mellitus; or - cardiovascular diseases, for example, cardiac hypertrophy, restenosis, and atherosclerosis, or such as arrhythmia; or - glomerulonephritis; or - myelodysplastic syndrome; or ischemic injury associated with myocardial infarctions, stroke and reperfusion injury; or - toxin-induced alcohol-related liver diseases; or - hematological diseases, for example, chronic anemia and aplastic anemia; or degenerative diseases of the musculoskeletal system, for example, osteoporosis and arthritis, or - aspirin-sensitive rhinosinusitis; or - cystic ibrosis; or - multiple sclerosis, or - renal diseases; or - cancer pain; or - cancer, in particular RB + ve tumors.